Metabolomic-based analysis reveals bile acid-mediated ovarian failure induced by low temperature in zebrafish.

As ectotherms, fish are highly sensitive to temperature fluctuations, which can profoundly impact their reproductive cycles. In this study, we investigated the fertility and histological characteristics of zebrafish ( Danio rerio) ovaries exposed to a temperature gradient ranging from the thermopreferendum temperature of the species, 27°C, to lower temperatures of 22°C, 20°C, and 13°C over a period of two weeks. Comparative metabolomic (six biological replicates for each temperature) and transcriptomic (four biological replicates for each temperature) analyses were conducted under the four temperature conditions. Results indicated that lower temperatures inhibited oocyte development and differential metabolites were involved in steroid hormone production, antioxidant function, and lipid and protein catabolism. Disrupted reproductive hormones, increased proteolysis, and lipid degradation significantly impeded oocyte development and egg maturation. Notably, a significant increase in bile acid content was noted in the ovaries of the cold-treated fish, indicating that bile acids play a critical role in ovarian failure. Overall, these findings provide valuable insights into the mechanisms governing the reproductive response of fish to cold stress.

Hydroxyl-aluminum pillared bentonite enhanced Mn(II) removal by chlorine oxidation.

Al-PILC was used to catalyze the chlorine oxidation of Mn(II) in aqueous solution. The effects of various catalysts, catalyst dosage, chlorine dosage, pH value, temperature and organic content on the oxidation process were investigated. Results show that 1.5 mg/L chlorine can quickly oxidize Mn(II) from 0.5 mg/L to less than 0.04 mg/L with 10 mg/L Al-PILC. Using catalysts with higher porosity and higher SA, increase in chlorine concentration, increase in catalyst dosage, higher pH, and higher temperature can significantly enhance the rate of Mn(II) catalytic oxidation. The Mn(II) oxidation process includes the homogeneous oxidation, catalytic oxidation on the surface of the catalysts and self-catalytic oxidation produced by the newly produced MnOx. Al-PILC surface provides active sites for chlorine oxidation Mn(II) in the water, and also provides binding sites for the newly produced MnOx, which has higher catalytic activity and thus has an self-catalytic oxidation effect. The higher the porosity and SA of Al-PILC, the more catalytic oxidation active sites and loading sites, and the better the catalytic oxidation effect. The study promotes the understanding of chlorine catalyzed oxidation Mn(II) in aqueous solution, but also provide important guide to study newly efficient catalysts to oxidize Mn(II) with chlorine in aqueous solution.

Ruthenium-catalyzed C-H functionalization of indoles and indolines with 7-azabenzonorbornadienes: access to aminodihydronaphthyl indoles and indolines.

Indoles, indolines and hydronaphthylamines are ubiquitous structural motifs in natural products, pharmaceuticals, and biologically active molecules. In this paper, we report the synthesis of aminodihydronaphthyl-substituted indoles and indolines via a Ru-catalyzed carbamoyl-directed C-H functionalization of indoles and indolines with 7-azabenzonorbornadienes. In the presence of Cu(OAc)2 and AgSbF6, [Ru(p-cymene)Cl2]2 catalyzes the reaction of 1-carbamoylindoles with 7-azabenzonorbornadienes to produce 2-(1-amino-1,2-dihydronaphthalen-2-yl)indoles. Under the same conditions, the reaction of 1-carbamoylindolines with 7-azabenzonorbornadienes affords 7-(1-amino-1,2-dihydronaphthalen-2-yl)indolines. In both cases, the reactions yield cis-configured products.

Realization of monolayer ZrTe5 topological insulators with wide band gaps.

Two-dimensional topological insulators hosting the quantum spin Hall effect have application potential in dissipationless electronics. To observe the quantum spin Hall effect at elevated temperatures, a wide band gap is indispensable to efficiently suppress bulk conduction. Yet, most candidate materials exhibit narrow or even negative band gaps. Here, via elegant control of van der Waals epitaxy, we have successfully grown monolayer ZrTe5 on a bilayer graphene/SiC substrate. The epitaxial ZrTe5 monolayer crystalizes in two allotrope isomers with different intralayer alignments of ZrTe3 prisms. Our scanning tunneling microscopy/spectroscopy characterization unveils an intrinsic full band gap as large as 254 meV and one-dimensional edge states localized along the periphery of the ZrTe5 monolayer. First-principles calculations further confirm that the large band gap originates from strong spin-orbit coupling, and the edge states are topologically nontrivial. These findings thus provide a highly desirable material platform for the exploration of the high-temperature quantum spin Hall effect.

Glycyrrhetinic acid blocks SARS-CoV-2 infection by activating the cGAS-STING signalling pathway.

BACKGROUND AND PURPOSE: Traditional Chinese medicine (TCM) played an important role in controlling the COVID-19 pandemic, but the scientific basis and its active ingredients are still weakly studied. This study aims to decipher the underlying anti-SARS-CoV-2 mechanisms of glycyrrhetinic acid (GA). EXPERIMENTAL APPROACH: GA's anti-SARS-CoV-2 effect was verified both in vitro and in vivo. Homogeneous time-resolved fluorescence assays, biolayer interferometry technology, and molecular docking were employed to examine interactions of GA with human stimulator of interferon genes (hSTING). Immunofluorescence staining, western blot, and RT-qPCR were used to investigate nuclear translocation of interferon regulatory factor 3 (IRF3) and levels of STING target genes. Pharmacokinetics of GA was studied in mice. KEY RESULTS: GA could directly bind to Ser162 and Tyr240 residues of hSTING, thus up-regulating downstream targets and activation of the STING signalling pathway. Such activation is crucial for limiting the replication of SARS-CoV-2 Omicron in Calu-3 cells and protecting against lung injury induced by SARS-CoV-2 Omicron infection in K18-ACE2 transgenic mice. Immunofluorescence staining and western blot indicated that GA increased levels of phosphorylated STING, phosphorylated TANK-binding kinase-1, and cyclic GMP-AMP synthase (cGAS). Importantly, GA increased nuclear translocation of IRF3. Pharmacokinetic analysis of GA in mice indicated it can be absorbed into circulation and detected in the lung at a stable level. CONCLUSION AND IMPLICATIONS: Activation of the cGAS-STING pathway through the GA-STING-IRF3 axis is essential for the antiviral activity of GA in mice, providing new insights into the potential translation of GA for treating SARS-CoV-2 in patients.

MiR-760 exerts a critical regulatory role in glioma proliferation, migration, and invasion by modulating MMP2 expression.

Background: Glioma represents the predominant subtype of brain tumor, characterized by an unfavorable prognosis. Current evidence indicates the involvement of microRNAs (miRNAs) in the initiation and progression of glioma malignancies. While miR-760 has been recognized in the context of tumorigenesis, its precise role in gliomas remains insufficiently explored. Methods: In this investigation, we harnessed the GSE25631 database to scrutinize the aberrant expression profiles of microRNAs, whereby the diminished expression of miR-760 in glioblastoma was validated. Our aim was to delineate the expression patterns of microRNA-760 (miR-760) and probe its prognostic significance within the realm of glioma. Employing quantitative real-time polymerase chain reaction, we ascertained the relative expression levels of miR-760 and MMP2 in glioma cell lines. The impact of miR-760 on cell proliferation, migration, and invasion was assessed through Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and Transwell assays. Bioinformatics analysis corroborated the downstream target gene of miR-760. Furthermore, a luciferase reporter experiment was conducted to pinpoint MMP2 as the direct target gene of miR-760. The assessment of MMP2 protein levels was accomplished through Western blotting and immunofluorescence techniques. Result: Our data unequivocally revealed a substantial reduction in miR-760 expression within glioma tissues and cell lines. Heightened miR-760 levels exerted a restraining influence on the proliferation, migration, and invasion capabilities of glioma cell lines. The outcomes of our bioinformatics analysis unveiled the ability of miR-760 to engage with and curtail MMP2 expression. Collectively, these findings posit that miR-760 exerts a restraining influence on glioma growth by orchestrating the upregulation of miR-760 along the miR-760/MMP2 axis. Conclusion: The delineation of the miR-760/MMP2 axis promises to broaden our comprehension of the intricate molecular mechanisms underpinning glioma proliferation and may unveil prospective therapeutic avenues for the management of glioma.

Phage therapy combats pan drug-resistant Acinetobacter baumannii infection safely and efficiently.

Phage therapy offers a promising approach to combat the growing threat of antimicrobial resistance. Yet, key questions remain regarding dosage, administration routes, combination therapy, and the causes of therapeutic failure. In this study, we focused on a novel lytic phage, ФAb4B, which specifically targeted the Acinetobacter baumannii strains with KL160 capsular polysaccharide, including the pan-drug resistant A. baumannii YQ4. ФAb4B exhibited the ability to effectively inhibit biofilm formation and eradicate mature biofilms independently of dosage. Additionally, it demonstrated a wide spectrum of antibiotic-phage synergy and did not show any cytotoxic or haemolytic effects. Continuous phage injections, both intraperitoneally and intravenously over 7 d, showed no acute toxicity in vivo. Importantly, phage therapy significantly improved neutrophil counts, outperforming ciprofloxacin. However, excessive phage injections suppressed neutrophil levels. The combinatorial treatment of phage-ciprofloxacin rescued 91% of the mice, a superior outcome compared to phage alone (67%). The efficacy of the combinatorial treatment was independent of phage dosage. Notably, prophylactic administration of the combinatorial regimen provided no protection, but even when combined with a delayed therapeutic regimen, it saved all the mice. Bacterial resistance to the phage was not a contributing factor to treatment failure. Our preclinical study systematically describes the lytic phage's effectiveness in both in vitro and in vivo settings, filling in crucial details about phage treatment against bacteriemia caused by A. baumannii, which will provide a robust foundation for the future of phage therapy.

A novel method for quantitative determination of multiple substances using Raman spectroscopy combined with CWT.

The identification of mixed solutions is a challenging and important subject in chemical analysis. In this paper, we propose a novel workflow that enables rapid qualitative and quantitative detection of mixed solutions. We use a methanol-ethanol mixed solution as an example to demonstrate the superiority of this workflow. The workflow includes the following steps: (1) converting Raman spectra into Raman images through CWT; (2) using MobileNetV3 as the backbone network, improved multi-label and multi-channel synchronization enables simultaneous prediction of multiple mixture concentrations; and (3) using transfer learning and multi-stage training strategies for training to achieve accurate quantitative analysis. We compare six traditional machine learning algorithms and two deep learning models to evaluate the performance of our new method. The experimental results show that our model has achieved good prediction results when predicting the concentration of methanol and ethanol, and the coefficient of determination R2 is greater than 0.999. At different concentrations, both MAPE and RSD outperform other models, which demonstrates that our workflow has outstanding analytical capabilities. Importantly, we have solved the problem that current quantitative analysis algorithms for Raman spectroscopy are almost unable to accurately predict the concentration of multiple substances simultaneously. In conclusion, it is foreseeable that this non-destructive, automated, and highly accurate workflow can further advance Raman spectroscopy.

E93 is indispensable for reproduction in ametabolous and hemimetabolous insects.

Ecdysone-induced protein 93 (E93), known as the 'adult-specifier' transcription factor in insects, triggers metamorphosis in both hemimetabolous and holometabolous insects. Although E93 is conserved in ametabolous insects, its spatiotemporal expression and physiological function remain poorly understood. In this study, we first discover that, in the ametabolous firebrat Thermobia domestica, the previtellogenic ovary exhibits cyclically high E93 expression, and E93 mRNA is broadly distributed in previtellogenic ovarioles. E93 homozygous mutant females of T. domestica exhibit severe fecundity deficiency due to impaired previtellogenic development of the ovarian follicles, likely because E93 induces the expression of genes involved in ECM (extracellular matrix)-receptor interactions during previtellogenesis. Moreover, we reveal that in the hemimetabolous cockroach Blattella germanica, E93 similarly promotes previtellogenic ovarian development. In addition, E93 is also essential for vitellogenesis that is necessary to guarantee ovarian maturation and promotes the vitellogenesis-previtellogenesis switch in the fat body of adult female cockroaches. Our findings deepen the understanding of the roles of E93 in controlling reproduction in insects, and of E93 expression and functional evolution, which are proposed to have made crucial contributions to the origin of insect metamorphosis.

Construction of ecological network in Qujing city based on MSPA and MCR models.

With the rapid advancement of urbanization and industrialization, ecological patches within cities and towns are fragmented and ecological corridors are cut off, regional ecological security is threatened and sustainable development is hindered. Building an ecological network that conforms to regional realities can connect fragmented patches, protect biodiversity and regional characteristics, and provide scientific reference for regional ecological protection and ecological network planning. By taking Qilin District, the main urban area of Qujing City as an example, and using geospatial data as the main data source, based on morphological spatial pattern analysis (MSPA) and minimum cumulative resistance (MCR), this study identified ecological source areas, extracted ecological corridors, and build & optimize ecological networks. (1) All landscape types are identified based on MSPA, the proportion of core area was the highest among all landscape types, which was 80.69%, combined with the connectivity evaluation, 14 important ecological source areas were selected. (2) 91 potential ecological corridors were extracted through MCR and gravity models, there were 16 important ones. (3) The network connectivity analysis method is used to calculate the α, ß, and γ indexes of the ecological network before optimization, which were 2.36, 6.5, and 2.53, while after optimization, α, ß and γ indices were 3.8, 9.5 and 3.5, respectively. The combined application of MSPA-MCR model and ecological network connectivity analysis evaluation is conducive to improving the structure and functionality of ecological network.

Prognostic utility of blood inflammation biomarkers before and after treatment on the survival of patients with locally advanced non-small cell lung cancer undergoing stereotactic body radiotherapy.

BACKGROUND AND OBJECTIVE: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significant and succinct indicators of systemic inflammation. We assessed the influence of stereotactic body radiotherapy (SBRT) on NLR and PLR in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We reviewed the medical data of patients with LA-NSCLC who underwent SBRT between 1 January 2013 and 31 December 2018. NLR and PLR values recorded at pre- and post-SBRT were examined. We assessed the correlation between pre/post-SBRT NLR and PLR and survival outcomes. The decision tree evaluation was conducted using Chi-square automatic detection. RESULTS: In total, 213 patients were included in the study with a median follow-up duration of 40.00 (ranging from 5.28 to 100.70) months. Upon dichotomization by a median, we identified that post-SBRT NLR > 5.5 and post-SBRT PLR > 382.0 were negatively associated with shorter overall survival (OS). In the multivariate assessment, post-SBRT PLR > 382.0 was the only factor. Based on post-SBRT PLR, tumor locations, and tumor stage, we categorized patients into low, medium, or high-risk groups. CONCLUSIONS: Post-SBRT PLR > 382.0 correlated with survival in patients undergoing SBRT. The decision tree model might play a role in future risk stratification to guide the clinical practice of individualized SBRT for LA-NSCLC.

Dual regulation of cytochrome P450 gene expression by two distinct small RNAs, a novel tasiRNA and miRNA, in Marchantia polymorpha.

The miR390-derived TAS3 trans-acting short-interfering RNAs (tasiRNAs) module represents a conserved RNA silencing pathway in the plant kingdom; however, its characterization in the bryophyte Marchantia polymorpha is limited. This study elucidated that MpDCL4 processes MpTAS3 double-stranded RNA (dsRNA) to generate tasiRNAs, primarily from the 5'- and 3'-ends of dsRNA. Notably, we discovered a novel tasiRNA, tasi78A, can negatively regulate a cytochrome P450 gene, MpCYP78A101. Additionally, tasi78A was abundant in MpAGO1, and transient expression assays underscored the role of tasi78A in repressing MpCYP78A101. A microRNA, miR11700, also regulates MpCYP78A101 expression. This coordinate regulation suggests a role in modulating auxin signaling at apical notches of gemma, influencing the growth and sexual organ development of M. polymorpha and emphasizing the significance of RNA silencing in MpCYP78A101 regulation. However, phylogenetic analysis identified another paralog of the CYP78 family, Mp1g14150, which may have a redundant role with MpCYP78A101, explaining the absence of noticeable morphological changes in loss-of-function plants. Taken together, our findings provide new insights into the combined regulatory roles of miR390/MpTAS3/miR11700 in controlling MpCYP78A101 and expand our knowledge about the biogenesis and regulation of tasiRNAs in M. polymorpha.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

Psychometric properties of the wellbeing literacy 6-item scale in Chinese military academy cadets.

Background: Positive psychology is a vibrant field of study, and conceptualizations of the components of well-being have received a great deal of attention from researchers. The study of well-being literacy thus provides an innovative perspective for enhancing and sustaining individuals' experiences of well-being. Objective: This study aimed to examine the psychometric properties of the wellbeing literacy 6-item (Well-Lit 6) scale in Chinese military academy cadets. Methods: A total of 3,218 undergraduate students from five military academies in China were recruited to complete questionnaires online. Results: (1) The items of the scale showed high discrimination; (2) The alpha coefficient of the scale was 0.986 and the split-half reliability was 0.981, indicating high homogeneous reliability and split-half reliability; (3) The scale model fitted well and displayed structural validity; (4) The correlation between well-being literacy and related indicators was significant, and the calibration correlation and convergent-discriminant validity of the scale were high; (5) After gradually adding demographic variables, known predictors factors and well-being literacy, the ∆R2 for subjective well-being, life satisfaction, depression, and anxiety ranged from 0.036 to 0.067, 0.184 to 0.340, and 0.009 to 0.017, respectively, showing high incremental validity; (6) the total well-being literacy scores differed significantly by gender, grade, and parenting style. Conclusion: The Chinese version of the Well-Lit 6 is reliable and valid in predicting and accessing the subjective well-being, life satisfaction, emotion regulation, and psychological resilience of Chinese military academy cadets.

Eldecalcitol protected osteocytes against ferroptosis of D-gal-induced senescent MLO-Y4 cells and ovariectomized mice.

BACKGROUND: Active vitamin D analog eldecalcitol is clinically applied in treatment of postmenopausal osteoporosis. This study aims to determine the role of eldecalcitol in the protection of osteocytes from senescence and the associated ferroptosis. METHODS: The MLO-Y4 osteocytes were exposed to D-gal inducing senescence. The ovariectomized (OVX) mice treated with D-gal using as an aging inducer were intraperitoneally injected with eldecalcitol. The multiplexed confocal imaging, fluorescence in situ hybridization and transmission electron microscopy were applied in assessing osteocytic properties. Immunochemical staining and immunoblotting were carried out to detect abundance and expression of molecules. RESULTS: The ablation of vitamin D receptor led to a reduction in amounts of osteocytes, a loss of dendrites, an increase in mRNA expression of SASP factors and in protein expression of senescent factors, as well as changes in mRNA expression of ferroptosis-related genes (PTGS2 & RGS4). Eldecalcitol reversed senescent phenotypes of MLO-Y4 cells shown by improving cell morphology and density, decreasing ß-gal-positive cell accumulation, and down-regulating protein expression (P16, P21 & P53). Eldecalcitol reduced intracellular ROS and MDA productions, elevated JC-1 aggregates, and up-regulated expression of Nrf2 and GPX4. Eldecalcitol exhibited osteopreserve effects in D-gal-induced aging OVX mice. The confocal imaging displayed its improvement on osteocytic network organization. Eldecalcitol decreased the numbers of senescent osteocytes at tibial diaphysis by SADS assay and attenuated mRNA expression of SASP factors as well as down-regulated protein expression of senescence-related factors and restored levels of ferroptotic biomarkers in osteocytes-enriched bone fraction. It reduced 4-HNE staining area, stimulated Nrf2-positive staining, and promoted nuclear translocation of Nrf2 in osteocytes of mice as well as inhibited and promoted protein expression of 4-HNE and Nrf2, respectively, in osteocytes-enriched bone fraction. CONCLUSIONS: The present study revealed the ameliorative effects of eldecalcitol on senescence and the associated ferroptosis of osteocytes, contributing to its preservation against osteoporosis of D-gal-induced senescent ovariectomized mice.

Efficiently tuning the electrical performance of PBTTT-C14 thin film viainsitucontrollable multiple precursors (Al2O3:ZnO) vapor phase infiltration.

Conjugated polymer-based organic/inorganic hybrid materials become the current research frontier and show great potential to integrate flexible polymers and rigid solid materials, which have been widely used in the field of various flexible electronics and optical devices. In this study, based on the multiple vapor phase infiltration (VPI) process, various precursor molecules (diethylzinc DEZ, trimethylaluminum TMA, H2O) are applied for thein situmodification of PBTTT-C14 films. The conductivity of the PBTTT-C14/Al2O3:ZnO (AZO) film is significantly enhanced, and the maximum value of conductivity is 1.16 S cm-1, which is eight orders of magnitude higher than the undoped PBTTT-C14 thin film. Here, the change of morphologies and crystalline states are analyzed via SEM, AFM, and XRD. And the chemical changes during the VPI process of PBTTT-C14 are characterized through Raman, XPS, and UV-vis. During the AZO VPI process, the formation of new ZnS matrix in the polymer subsurface can generate new additional electron conduction pathways through the crosslinking of polymer chains with inorganic materials, and the addition of Al2O3can bring about the increase of average grain size of ZnO crystals, which is also benefit to the conductivity increase of PBTTT-C14 thin film. Generally, the synergistic effect between the inorganic and polymer constituents results in the significantly enhancement of the conductivity of PBTTT-C14/AZO thin films.

Motorized and non-motorized mixed traffic characteristics and lateral opening spacing calculation for the section of arterial highway through small towns.

A large number of motor vehicles and non-motorized vehicles mixed in the section of arterial highway crossing the town leads to many traffic problems. Therefore, it is necessary to set up a side divider between motorized and non-motorized lanes, and the appropriate spacing of lateral crossing openings to meet the needs of non-motorized vehicles crossing the highway has become a key issue that must be resolved. This paper investigates the traffic flow characteristics of mixed traffic flow on arterial highways through small town sections, and from the two dimensions of highway access efficiency and the psychological characteristics of cyclists, it calibrates the setting range of the spacing of non-motorized lateral crossing openings under different design speeds, which is used to regulate the behavior of non-motorized vehicles crossing the street, improve the safety level of the highway, reduce the lateral interference of the highway, and improve the road access efficiency. The accuracy of the research results is verified by microscopic simulation experiments, which proves that they can meet good expectations in practical engineering. The research results have theoretical significance and reference value for improving the status quo of machine-non-mixed traffic in the section of arterial highway passing through small towns, and enhancing the efficiency and safety of highway traffic. It also provides corresponding reference for the areas facing similar problems worldwide.