Experimental investigation on dynamic deformation characteristics of the overlying strata in backfilling strip mining at different time scales.

The dynamic subsidence disaster caused by underground mining of coal resources is a complex spatiotemporal process, which is a common disaster in mining areas. The backfilling strip mining technology is a green and sustainable coal mining method, which has been commonly used to reduce the subsidence disaster of the overlying strata and protect surface buildings. The transient deformation is the main reason of surface buildings damage; therefore, in this study, the similar material model was used to research dynamic deformation characteristics of the overlying strata in backfilling strip mining at different time scales, and the optical image method was employed to monitor and obtain the movement data of the overlying strata automatically. The data analysis shows that there is a time-scale effect in mining subsidence. The deformation of the overlying strata increases instantaneously at a certain time under the monitoring of small time scale, and this phenomenon gradually disappears as time scales increase. According to the subsidence velocity of small time scale, the subsidence state of the overlying strata can be further divided into the abrupt subsidence state and the gentle subsidence state. This is really significant for promoting the development of the backfilling strip mining technology and preventing the damage of surface buildings.

Preparation and measurement of a sandwiched Sn atomic beam source for laser resonance ionization mass spectrometry.

Isotope analysis of Sn plays a crucial role in geochemical studies and in monitoring nuclear contamination. Nevertheless, prevalent analytical techniques for examining Sn isotopes encounter the issue of isobaric interference, markedly impacting the accuracy of the test results. Laser resonance ionization mass spectrometry (LRIMS) can effectively overcome the difficulties associated with the isobaric interference inherent in commercial mass spectrometry. In this paper, different amounts of Sn were prepared on Re filaments by electrodeposition and tested via LRIMS. The results showed that the average detection efficiency of LRIMS decreased with increasing total Sn content from 1 µg to 4 µg, and the fluctuations in the test results among the samples increased significantly. Therefore, the electrodeposition process, as well as the composition and morphology of the deposits were characterized by SEM, EDS and XPS; results showed that the degradation of the samples with increasing Sn content was attributed to the complexity of the composition, micro-structure, valence of the deposits, and the interference of various elements. To cope with the anomalies encountered above, the deposits were heat-treated at 600 °C in a hydrogen atmosphere to eliminate detrimental impurities, like Cl, and Sn was effectively reduced to an almost singular atomic state. Furthermore, a titanium layer was covered on the surface of the heat-treated deposit by magnetron sputtering. Ultimately, a highly efficient and stable Sn atomic beam source with a sandwiched structure has been successfully developed and exhibits broad application prospect.

FGF21 overexpression alleviates VSMC senescence in diabetic mice by modulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-ß-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-ß-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.

Unearthing naturally-occurring cyclic antibacterial peptides and their structural optimization strategies.

Natural products with antibacterial activity are highly desired globally to combat against multidrug-resistant (MDR) bacteria. Antibacterial peptide (ABP), especially cyclic ABP (CABP), is one of the abundant classes. Most of them were isolated from microbes, demonstrating excellent bactericidal effects. With the improved proteolytic stability, CABPs are normally considered to have better druggability than linear peptides. However, most clinically-used CABP-based antibiotics, such as colistin, also face the challenges of drug resistance soon after they reached the market, urgently requiring the development of next-generation succedaneums. We present here a detail review on the novel naturally-occurring CABPs discovered in the past decade and some of them are under clinical trials, exhibiting anticipated application potential. According to their chemical structures, they were broadly classified into five groups, including (i) lactam/lactone-based CABPs, (ii) cyclic lipopeptides, (iii) glycopeptides, (iv) cyclic sulfur-rich peptides and (v) multiple-modified CABPs. Their chemical structures, antibacterial spectrums and proposed mechanisms are discussed. Moreover, engineered analogs of these novel CABPs are also summarized to preliminarily analyze their structure-activity relationship. This review aims to provide a global perspective on research and development of novel CABPs to highlight the effectiveness of derivatives design in identifying promising antibacterial agents. Further research efforts in this area are believed to play important roles in fighting against the multidrug-resistance crisis.

Characterization of sexual maturity-associated N6-methyladenosine in boar testes.

BACKGROUND: The health and size of the testes are crucial for boar fertility. Testicular development is tightly regulated by epigenetics. N6-methyladenosine (m6A) modification is a prevalent internal modification on mRNA and plays an important role in development. The mRNA m6A methylation in boar testicular development still needs to be investigated. RESULTS: Using the MeRIP-seq technique, we identify and profile m6A modification in boar testes between piglets and adults. The results showed 7783 distinct m6A peaks in piglets and 6590 distinct m6A peaks in adults, with 2,471 peaks shared between the two groups. Enrichment of GO and KEGG analysis reveal dynamic m6A methylation in various biological processes and signalling pathways. Meanwhile, we conjointly analyzed differentially methylated and expressed genes in boar testes before and after sexual maturity, and reproductive related genes (TLE4, TSSK3, TSSK6, C11ORF94, PATZ1, PHLPP1 and PAQR7) were identified. Functional enrichment analysis showed that differential genes are associated with important biological functions, including regulation of growth and development, regulation of metabolic processes and protein catabolic processes. CONCLUSION: The results demonstrate that m6A methylation, differential expression and the related signalling pathways are crucial for boar testicular development. These results suggest a role for m6A modification in boar testicular development and provided a resource for future studies on m6A function in boar testicular development.

Novel pathway of stabilized Cu2S volatilization by derivated CH3Cl.

Stabilized heavy metals-containing phases and low chlorine utilization limit heavy metals chlorination reactions. The traditional method of adding chlorinating agents can promote heavy metals chlorination volatilization, but the limiting factor has not been resolved and more chlorides are emitted. Herein, a new reaction pathway to promote heavy metals chlorination volatilization through the transformation of stabilized heavy metals-containing phases and chlorine species by the addition of biomass at the sintering is first reported. The Cu volatilization efficiency increased sharply from 50.50% to 93.21% compared with the control, Zn, Pb, and Cd were nearly completely volatilized. Results show that the biomass carbonization process was more important for Cu chlorination volatilization. Stabilized heavy metals-containing phases were converted from Cu2S to CuO and Cu2O with the biochar and oxygen, increasing the activity of Cu. The chlorine species KCl reacted with CH3-containing groups to form CH3Cl, which reacted with CuO with a lower Delta G than HCl and Cl2, increasing the tendency for the conversion of CuO to CuCl. Cu chlorination volatilization process, following shrinking core kinetic model and controlled by chemical reactions. The outcomes fundamentally addresses the limiting step for heavy metals chlorination volatilization, supporting the incineration fly ash harmless treatment.

Effect of Telitacicept on Circulating Gd-IgA1 and IgA-Containing Immune Complexes in IgA Nephropathy.

Introduction: Telitacicept, a transmembrane activator and cyclophilin ligand interactor (TACI) fusion protein targeting B cell activating factor and a proliferation-inducing ligand (APRIL), has proven efficacy in treating Immunoglobulin A (IgA) nephropathy (IgAN). However, serum biomarkers that could predict the clinical response during the treatment remain unclear. Methods: Plasma samples from 24 participants in the phase 2 clinical trial were collected at baseline and after 4, 12, and 24 weeks; with 8 participants in the placebo group, 9 in the 160 mg group, and 7 in the 240 mg group. We measured the levels of galactose-deficient-IgA1 (Gd-IgA1), IgA-containing immune complexes, C3a, C5a, and sC5b-9. The association between the changes in these markers and proteinuria reduction was analyzed. Results: After 24 weeks of treatment, Gd-IgA1 decreased by 43.9% (95% confidence interval: 29.8%, 55.1%), IgG-IgA immune complex by 31.7% (14.4%, 45.5%), and poly-IgA immune complex by 41.3% (6.5%, 63.1%) in the 160 mg group; Gd-IgA1 decreased by 50.4% (38.6%, 59.9%), IgG-IgA immune complex decreased by 42.7% (29.5%, 53.4%), and poly-IgA immune complex decreased by 67.2% (48.5%,79.1%) in the 240 mg group. There were no significant changes in the circulatory C3a, C5a, or sC5b-9 levels during telitacicept treatment. Decreases in both plasma Gd-IgA1 and IgG-IgA or poly-IgA immune complexes were associated with proteinuria reduction. In turn, IgG-IgA or poly-IgA immune complexes showed a dose-dependent effect, consistent with proteinuria reduction during telitacicept treatment. Conclusion: Telitacicept lowered both circulating Gd-IgA1 and IgA-containing immune complexes, whereas IgA immune complex levels were more consistent with decreased proteinuria.

Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation.

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-ß) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-ß promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-ß blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumour immune responses. In conclusion, M2-TAM-derived TGF-ß promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-ß receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.

Is lactic acid a misunderstood trigger of gout attack for a century?

A gout attack could be viewed as a nucleation event. Many reports have shown that the typical molecular structure of crystallization inhibitors usually contains carboxyl and hydroxyl groups, which could interact with solute molecules through hydrogen bonding, thereby suppressing the nucleation and growth of crystals. Since 1923, l-lactic acid (LA), a molecule with structural features of inhibitors, has been speculated to be a trigger for acute gout because metabolized LA temporarily reduces uric acid excretion and leads to a slow increase in serum uric acid concentration. However, many cases of gout presumably triggered by elevated lactate in a very short period of 4 h are often inexplicable. Here, we present the unexpected result that LA has a significant "opposite effect" on the nucleation and growth of gouty pathological crystals, which is that as the concentration of the additive LA increases, the nucleation and growth of the crystals is suppressed and then facilitated. This approach may help our clarifying the long-standing "misunderstandings" and further understanding the association between metabolized LA and increased risk of gout attacks. Finally, a novel mechanism called "tailed-made occupancy (TMO)" was used to explain the nucleation and crystallization effects of LA on sodium urate monohydrate (MSUM).

Facile construction of sandwich ELISA based on double-nanobody for specific detection of α-hemolysin in food samples.

α-hemolysin (Hla), a toxin secreted by Staphylococcus aureus (S. aureus), has been proved to be involved in the occurrence and aggravation of food poisoning. Hence, it is quite essential to establish its rapid detection methods to guarantee food safety. Sandwich ELISA based on nanobody is well known to be viable for toxins, but there is absence of nanobody against Hla, let alone a pair for it. Therefore, in this paper, we screened specific nanobodies by bio-panning and obtained the optimal nanobody pair for sandwich ELISA firstly. Then, RANbody, a novel nanobody owning both recognition and catalytic capability, is generated in a single step and at low cost through molecular recombination technology. Subsequently, sandwich ELISA was developed to detect Hla based on the nanobody and RANbody, that not only eliminated the use of secondary antibodies and animal-derived antibody, but also reduced detection time and cost, compared with traditional sandwich ELISA. Lastly, the performance has been evaluated, especially for specificity which showed no response to other hemolysins and a low limit of detection of 10 ng/mL. Besides, the proposed sandwich ELISA exhibits favorable feasibility and was successfully employed for the detection of Hla in milk and pork samples.

Exploring FGFR signaling inhibition as a promising approach in breast cancer treatment.

As our grasp of cancer genomics deepens, we are steadily progressing towards the domain of precision medicine, where targeted therapy stands out as a revolutionary breakthrough in the landscape of cancer therapeutics. The fibroblast growth factor receptors (FGFR) pathway has been unveiled as a fundamental instigator in the pathophysiological mechanisms underlying breast carcinoma, paving the way for the exhilarating development of precision-targeted therapeutics. In the pursuit of exploring inhibitors that specifically target the FGFR signaling pathways, a multitude of kinase inhibitors targeting FGFR has been assiduously engineered to address the heterogeneous landscape of human malignancies. This review offers an exhaustive exploration of aberrations within the FGFR pathway and their functional implications in breast cancer. Additionally, we delve into cutting-edge therapeutic approaches for the treatment of breast cancer patients bearing FGFR alterations and the management of toxicity associated with FGFR inhibitors. Furthermore, our contemplation of the evolution of cutting-edge FGFR inhibitors foresees their potential to spearhead innovative therapeutic approaches in the ongoing combat against cancer.

Automated and miniaturized screening of antibiotic combinations via robotic-printed combinatorial droplet platform.

Antimicrobial resistance (AMR) has become a global health crisis in need of novel solutions. To this end, antibiotic combination therapies, which combine multiple antibiotics for treatment, have attracted significant attention as a potential approach for combating AMR. To facilitate advances in antibiotic combination therapies, most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however, there remains a need for automated high-throughput platforms that can create and examine antibiotic combinations on-demand, at scale, and with minimal reagent consumption. To address these challenges, we have developed a Robotic-Printed Combinatorial Droplet (RoboDrop) platform by integrating a programmable droplet microfluidic device that generates antibiotic combinations in nanoliter droplets in automation, a robotic arm that arranges the droplets in an array, and a camera that images the array of thousands of droplets in parallel. We further implement a resazurin-based bacterial viability assay to accelerate our antibiotic combination testing. As a demonstration, we use RoboDrop to corroborate two pairs of antibiotics with known interactions and subsequently identify a new synergistic combination of cefsulodin, penicillin, and oxacillin against a model E. coli strain. We therefore envision RoboDrop becoming a useful tool to efficiently identify new synergistic antibiotic combinations toward combating AMR.

Massively Reconstructing Hydrogen Bonding Network and Coordination Structure Enabled by a Natural Multifunctional Co-Solvent for Practical Aqueous Zn-Ion Batteries.

The practical application of aqueous Zn-ion batteries (AZIBs) is hindered by the crazy Zn dendrites growth and the H2O-induced side reactions, which rapidly consume the Zn anode and H2O molecules, especially under the lean electrolyte and Zn anode. Herein, a natural disaccharide, d-trehalose (DT), is exploited as a novel multifunctional co-solvent to address the above issues. Molecular dynamics simulations and spectral characterizations demonstrate that DT with abundant polar -OH groups can form strong interactions with Zn2+ ions and H2O molecules, and thus massively reconstruct the coordination structure of Zn2+ ions and the hydrogen bonding network of the electrolyte. Especially, the strong H-bonds between DT and H2O molecules can not only effectively suppress the H2O activity but also prevent the rearrangement of H2O molecules at low temperature. Consequently, the AZIBs using DT30 electrolyte can show high cycling stability even under lean electrolyte (E/C ratio = 2.95 µL mAh-1), low N/P ratio (3.4), and low temperature (-12 °C). As a proof-of-concept, a Zn||LiFePO4 pack with LiFePO4 loading as high as 506.49 mg can be achieved. Therefore, DT as an eco-friendly multifunctional co-solvent provides a sustainable and effective strategy for the practical application of AZIBs.

Fabrication of polydopamine/rGO Membranes for Effective Radionuclide Removal.

In this work, a novel polydopamine/reduced graphene oxide (PDA/rGO) nanofiltration membrane was prepared to efficiently and stably remove radioactive strontium ions under an alkaline environment. Through the incorporation of PDA and thermal reduction treatment, not only has the interlayer spacing of graphene oxide (GO) nanosheets been appropriately regulated but also an improved antiswelling property has been achieved. The dosage of GO, reaction time with PDA, mass ratio of PDA to GO, and thermal treatment temperature have been optimized to achieve a high-performance PDA/rGO membrane. The resultant PDA/rGO composite membrane has exhibited excellent long-term stability at pH 11 and maintains a steady strontium rejection of over 90%. Moreover, the separation mechanism of the PDA/rGO membrane has been systematically investigated and determined to be a synergistic effect of charge repulsion and size exclusion. Results have indicated that PDA/rGO could be considered as a promising candidate for the separation of Sr2+ ions from nuclear industry wastewater.

Corrigendum: Which headache disorders can be diagnosed concurrently? An analysis of ICHD3 criteria using prime encoding system.

[This corrects the article DOI: 10.3389/fneur.2023.1221209.].

Endodontic management considerations for Type III dens invaginatus based on anatomical characteristics: A case series.

Dens invaginatus (DI) is a developmental anomaly of the teeth characterised by the in-folding of the enamel into the dentin. Oehlers' Type III DI is the most serious form, in which the inherently invaginated channels communicate with periodontal and dental pulp tissue, increasing the risk of bacterial contamination. However, varying and complex anatomical features make diagnosis and treatment challenging. Conventional endodontic therapies promote healing by avoiding unnecessary interventions (e.g., surgical or other invasive treatments). Radiographic examination can reveal the structural details of such malformations. We obtained multiple procedural details for treating Type III DI based on radiographic analyses from our clinical experience. In addition, we introduce a new classification strategy for the management of Type III DI that is more applicable to treatment needs. This study aimed to discuss the anatomical features and current treatment considerations of Type III DI.

Efficient production of l-glutathione by whole-cell catalysis with ATP regeneration from adenosine.

l-glutathione (GSH) is an important tripeptide compound with extensive applications in medicine, food additives, and cosmetics industries. In this work, an innovative whole-cell catalytic strategy was developed to enhance GSH production by combining metabolic engineering of GSH biosynthetic pathways with an adenosine-based adenosine triphosphate (ATP) regeneration system in Escherichia coli. Concretely, to enhance GSH production in E. coli, several genes associated with GSH and  l-cysteine degradation, as well as the branched metabolic flow, were deleted. Additionally, the GSH bifunctional synthase (GshFSA) and GSH ATP-binding cassette exporter (CydDC) were overexpressed. Moreover, an adenosine-based ATP regeneration system was first introduced into E. coli to enhance GSH biosynthesis without exogenous ATP additions. Through the optimization of whole-cell catalytic conditions, the engineered strain GSH17-FDC achieved an impressive GSH titer of 24.19 g/L only after 2 h reaction, with a nearly 100% (98.39%) conversion rate from the added  l-Cys. This work not only unveils a new platform for GSH production but also provides valuable insights for the production of other high-value metabolites that rely on ATP consumption.

Targeting the gut microbiota to enhance the antitumor efficacy and attenuate the toxicity of CAR-T cell therapy: a new hope?

Chimeric antigen receptor (CAR) -T cell therapy has achieved tremendous efficacy in the treatment of hematologic malignancies and represents a promising treatment regimen for cancer. Despite the striking response in patients with hematologic malignancies, most patients with solid tumors treated with CAR-T cells have a low response rate and experience major adverse effects, which indicates the need for biomarkers that can predict and improve clinical outcomes with future CAR-T cell treatments. Recently, the role of the gut microbiota in cancer therapy has been established, and growing evidence has suggested that gut microbiota signatures may be harnessed to personally predict therapeutic response or adverse effects in optimizing CAR-T cell therapy. In this review, we discuss current understanding of CAR-T cell therapy and the gut microbiota, and the interplay between the gut microbiota and CAR-T cell therapy. Above all, we highlight potential strategies and challenges in harnessing the gut microbiota as a predictor and modifier of CAR-T cell therapy efficacy while attenuating toxicity.