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:To promote the resource utiiization of zinccontaining metallurgical dust and sludge in ron and steel industry, the zinccontaining metallurgccal dust and sludge with ron content of 30. 38% and zinc content of 4. 79% was studed by microwave reduction roasting-magnetic separaiion test. The experimental resutts show that t is difficult to reaize the effective separation of zinc and ron in Yin--containing metallurgccal dust and sludge by direct magneto separation wrthout roasting and convenional muffle furnace reduction roasting-magnetic separaion. When the microwave muffle furnace roasiing at 700 C for 15 min. The main phase in the roasted product Is Fe. When the magnetic field intenstty of the roasted product Is 150 mT,the zinc and ron in the zinccontaining metallurgccal dust can achieve better separaion. The concentrate index obtained by magnetic separation:the zinc content Is 2. 73%,the ron content Is 57. 84%, the ron recovery rate ss 88. 67%, tailings index of magneic separaion: the ron content Is 9.54%, the zinc content ss 9. 85 %, the zinc recovery rate Is 61. 72%. [ABSTRACT FROM AUTHOR]

Tris(3-hydroxypropyl)phosphine (THPP) was shown to be a more powerful reductant than tris(2-carboxyethyl)phosphine (TCEP), but its oxidation kinetics and mechanisms were scarcely investigated. The reduction of single electron oxidant [IrCl6]2− by THPP was thus investigated comparatively and shown to follow overall second-order kinetics. The established logk′ versus pH profiles for THPP and TCEP were different, where k′ is the observed second-order rate constant. THPP was oxidized to (HOCH2CH2CH2)3PO, confirmed by 1H NMR spectroscopy, which is in line with the determined stoichiometry. On the other hand, the proposed reaction mechanism is similar to that suggested for the TCEP reaction. The reactivity of THPP was derived, enabling a reactivity comparison with TCEP at physiological pH. Surprisingly, the measured activation parameters for the reduction of [IrCl6]2− by P(CH2CH2CH2OH)3 and P(CH2CH2CO2−)3 were essentially identical, providing information on the transition state and on the electron transfer mode. This work also defines the pKa value of THPP under well-defined conditions (pKa = 6.97 ± 0.05 at 25.0 °C and 1.0 M ionic strength) as derived by the kinetic approach. [ABSTRACT FROM AUTHOR]

To realize the low-carbon, environmentally protection and efficient resource utilization of metallurgical dust containing zinc in iron and steel enterprises, the reduction roasting-magnetic separation of metallurgical dust containing zinc with iron content of 30. 38% and zinc content of 4. 79% was studied. The experimental results show that the direct magnetic separation of metallurgical dust containing zinc is difficult to achieve effective separation of zinc and iron. Under the conditions of roasting temperature of 950 °C, roasting time of 20 min and magnetic separation intensity of 100 mT. The iron recovery rate of magnetic separation concentrate is 79.50%, the iron content is 57. 00%,and the zinc content is 2. 45%. The zinc recovery rate of magnetic separation taillings is 71. 06%, the zinc content is 9. 92%, and the iron content is 16. 81% . The separation rates of zinc and iron is better. The concentrate in the magnetic separation product is mainly composed of elemental Fe, and the tailings are mainly composed of SiO2 and ZnO. [ABSTRACT FROM AUTHOR]

The tetC gene has been found to be one of the most widely distributed tetracycline resistance (tet) genes in various environmental niches, but the detailed dissemination mechanisms are still largely unknown. In the present study, 11 tetC -containing Aeromonas media strains were isolated from an aerobic biofilm reactor under oxytetracycline stresses, and the genome of one strain was sequenced using the PacBio RSII sequencing approach to reveal the genetic environment of tetC. The tetC gene was carried by an IS 26 composite transposon, named Tn 6434. The tetC -carrying Tn 6434 structure was detected in all of the A. media strains either in a novel plasmid pAeme2 (n =9) or other DNA molecules (n =2) by PCR screening. The NCBI database searching result shows that this structure was also present in the plasmids or chromosomes of other 13 genera, indicating the transferability of Tn 6434. Inverse PCR and sequencing confirmed that Tn 6434 can form a circular intermediate and is able to incorporate into a preexisting IS 26 element, suggesting that Tn 6434 might be responsible for the dissemination of tetC between different DNA molecules. This study will be helpful in uncovering the spread mechanism of tet genes in water environments. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Ultrafine Fe 2 O 3 nanorods anchored on graphene oxide (GO) are synthesized by a one-pot route under mild conditions in presence of KMnO 4 and Ni foam. Ni foam is beneficial for the formation of Fe 2 O 3 rather than FeOOH under otherwise the same conditions, while KMnO 4 accelerates the hydrolysis of FeCl 3 , which promotes the nucleation of Fe 2 O 3 and the achievement of uniform ultra-small morphology thereby. As an anode material for lithium-ion batteries, the Fe 2 O 3 /GO manifests a reversible capacity of 1004 mA h g−1after 500 cycles at 200 mA g−1, and even presents a high reversible capacity of 722 mA h g−1 at 1600 mA g−1. The excellent electrochemical properties of Fe 2 O 3 /GO are attributed to the ultrafine nanorods of Fe 2 O 3 and the strong interaction between Fe 2 O 3 and GO, which can reduce the diffusion distance of Li+ ions, enlarge the electrode/electrolyte contact area and improve the cyclic stability of iron oxide. Graphical abstract Image 1 Highlights • Ultrafine α-Fe 2 O 3 nanorods anchored on graphene oxide surface are readily obtained. • The preparation condition was mild in presence of nickel foam (NF) and KMnO 4. • Formation of α-Fe 2 O 3 phase and KMnO 4 helps achieving a uniform and small morphology. • The α-Fe 2 O 3 /graphene oxide exhibits excellent electrochemical performance in LIBs. [ABSTRACT FROM AUTHOR]

Abstract Recently, the rarely reported tet (31) tetracycline resistance determinant was commonly found in Aeromonas salmonicida , Gallibacterium anatis , and Oblitimonas alkaliphila isolated from farming animals and related environment. However, its distribution in other bacteria and potential molecular dissemination mechanism in environment are still unknown. The purpose of this study was to investigate the potential mechanism underlying dissemination of tet (31) by analysing the tet (31)-carrying fragments in A. caviae strains isolated from an aerobic biofilm reactor treating oxytetracycline bearing wastewater. Twenty-three A. caviae strains were screened for the tet (31) gene by polymerase chain reaction (PCR). Three strains (two harbouring tet (31), one not) were subjected to whole genome sequencing using the PacBio RSII platform. Seventeen A. caviae strains carried the tet (31) gene and exhibited high resistance levels to oxytetracycline with minimum inhibitory concentrations (MICs) ranging from 256 to 512 mg/L. tet (31) was comprised of the transposon Tn 6432 on the chromosome of A. caviae , and Tn 6432 was also found in 15 additional tet (31)-positive A. caviae isolates by PCR. More important, Tn 6432 was located on an integrative conjugative element (ICE)-like element, which could mediate the dissemination of the tet (31)-carrying transposon Tn 6432 between bacteria. Comparative analysis demonstrated that Tn 6432 homologs with the structure IS CR2 - ∆phzF - tetR (31)- tet (31)- ∆glmM - sul2 were also carried by A. salmonicida , G. anatis , and O. alkaliphila , suggesting that this transposon can be transferred between species and even genera. This work provides the first report on the identification of the tet (31) gene in A. caviae , and will be helpful in exploring the dissemination mechanisms of tet (31) in water environment. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract: Picrasma quassioides (D. Don) Benn. is a widely used traditional Chinese medicine for anti‐inflammation and antibiosis. Canthinone and β‐carboline alkaloids are the main characteristic constituents that possess diverse pharmacological effects, such as anti‐inflammatory and anti‐infectious properties. In this study, bioautography in thin‐layer chromatography indicated that the antiradical activity compound may be alkaloids. Then, a simple, fast, and efficient method was established for the separation and purification of two types of alkaloids from P. quassioides by mass‐spectrometry‐directed autopurification system. Eight alkaloids were isolated and purified in this one‐step methodology. Among them, five compounds (3, 95.1%, 58.8 mg; 4, 98.4%, 71.7 mg; 6, 97.8%, 365.4 mg; 7, 97.7%, 172.7 mg; 8, 98.2%, 180.3 mg) were obtained in large amounts with extremely high purities. Then, the antiradical activities of the isolates showed that 4‐methoxy‐5‐hydroxycanthin‐6‐one (6) exhibited obvious 1,1‐diphenyl‐2‐picryl‐hydrazyl free radical scavenging activity with an IC50 value of 84.037 μM. This study offers a new method for the preparation of targeted bioactive alkaloids in P. quassioides. This work also provides a reference for the separation of other targeted chemical components with potential activities from traditional Chinese herbal medicines. [ABSTRACT FROM AUTHOR]

• Exposure to PS+AMI significantly increased the SOD and CAT activities. • More severe gut damage was observed in the PS+AMI group. • Exposure to PS+AMI altered the gut bacterial communities of zebrafish. • Exposure to PS+AMI disordered the predicted metabolic functions of gut microbiota. The potential toxicity of microplastics (MPs) and hydrophilic pharmaceuticals to aquatic organisms has recently raised great public concern, yet their combined effects on aquatic organisms remain largely unknown. Herein, the combined effects of MPs and the commonly prescribed amitriptyline hydrochloride (AMI) on the intestinal tissue and gut microbiota of zebrafish (Danio rerio) were investigated. Adult zebrafish were exposed to microplastics (polystyrene, PS, 440 µg/L), AMI (2.5 µg/L), PS+AMI (440 µg/L PS + 2.5 µg/L AMI), and dechlorinated tap water (control) for 21 days, respectively. Our results showed that zebrafish rapidly ingested PS beads and accumulated them in the gut. Exposure to PS+AMI significantly enhanced the SOD and CAT activities compared to the control group, suggesting that combined exposure might increase ROS production in the zebrafish gut. Exposure to PS+AMI led to severe gut injuries, including cilia defects, partial absence and cracking of intestinal villi. Exposure to PS+AMI caused shifts in the gut bacterial communities, increasing the abundance of Proteobacteria and Actinobacteriota , and decreasing the abundance of Firmicutes, Bacteroidota and beneficial bacteria Cetobacterium , which caused dysbiosis in the gut microbiota, and subsequently may induce intestinal inflammation. Furthermore, exposure to PS+AMI disordered the predicted metabolic functions of gut microbiota, but functional changes in the PS+AMI group at KEGG level 1 and level 2 were not significantly different from those in the PS group. The results of this study extend our knowledge of the combined effects of MPs and AMI on the health of aquatic organisms, and will be helpful in assessing the combined effects of MPs and tricyclic antidepressants on aquatic organisms. [ABSTRACT FROM AUTHOR]

Studies on antibiotic production wastewater have shown that even a single antibiotic can select for multidrug resistant bacteria in aquatic environments. It is speculated that plasmids are an important mechanism of multidrug resistance (MDR) under high concentrations of antibiotics. Herein, two metagenomic libraries were constructed with plasmid DNA extracted from cultivable microbial communities in a biological wastewater treatment reactor supplemented with 0 (CONTROL) or 25 mg/L of oxytetracycline (OTC-25). The OTC-25 plasmidome reads were assigned to 72 antibiotic resistance genes (ARGs) conferring resistance to 13 types of antibiotics. Dominant ARGs, encoding resistance to tetracycline, aminoglycoside, sulfonamide, and multidrug resistance genes, were enriched in the plasmidome under 25 mg/L of oxytetracycline. Furthermore, 17 contiguous multiple-ARG carrying contigs (carrying ≥ 2 ARGs) were discovered in the OTC-25 plasmidome, whereas only nine were found in the CONTROL. Mapping of the OTC-25 plasmidome reads to completely sequenced plasmids revealed that the conjugative IncU resistance plasmid pFBAOT6 of Aeromonas caviae, carrying multidrug resistance transporter (pecM), tetracycline resistance genes (tetA, tetR), and transposase genes, might be a potential prevalent resistant plasmid in the OTC-25 plasmidome. Additionally, two novel resistant plasmids (containing contig C301682 carrying multidrug resistant operon mexCD-oprJ and contig C301632 carrying the tet36 and transposases genes) might also be potential prevalent resistant plasmids in the OTC-25 plasmidome. This study will be helpful to better understand the role of plasmids in the development of MDR in water environments under high antibiotic concentrations. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cell (iPSC) technology has enabled modeling of human diseases using patient-derived cells with relevant genetic background. iPSC-derived 3D brain organoids self-organize and resemble the cytoarchitecture of in vivo brain tissue, making them attractive tools for modeling Alzheimer's disease (AD). Brain organoids (BOs) contain multiple human brain cell types, enabling the study of cell–cell interactions that drive AD progression. Human iPSC-derived BOs may reveal human-specific disease phenotypes and molecular mechanisms that are not recapitulated in animal models. Progression of Alzheimer's disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell–cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • The oxidation of TCEP by [IrCl 6 ]2− has been investigated kinetically over a wide pH range. • Observed second-order rate constant vs pH profile has been established. • Reaction mechanism involving phosphine radical cations is proposed and convincing. • The reactivity of the TCEP species towards an oxidant is deciphered for the first time. Despite of wide applications of tris(2-carboxyethyl)phosphine (TCEP) as a reductant, the reductions of single electron oxidants by TCEP are poorly understood mechanistically. Herein the reduction of [IrCl 6 ]2− by TCEP was thus investigated kinetically over a wide pH range at 1.0 M ionic strength. Overall second-order kinetics was proved for the reduction, being first-order with respect to both Ir(IV) and TCEP, respectively. The redox stoichiometry was determined to be Δ[Ir(IV)]:Δ[TCEP] = 2:1 and the corresponding phosphine oxide (TCEPO) was identified as the oxidation product of TCEP by 1H NMR spectroscopy. A reaction mechanism was rationalized in term of parallel reactions of [IrCl 6 ]2− with all the TCEP protolysis species being as the rate-determining steps, in which phosphine radical cations were involved as the transient intermediates. Rate constants of the rate-determining steps were calculated, rendering a reactivity trend for the five TCEP species: P(CH 2 CH 2 CO 2 −) 3 ≫ +HP(CH 2 CH 2 CO 2 −) 3 ≈ +HP(CH 2 CH 2 CO 2 −) 2 (CH 2 CH 2 CO 2 H) ≫ +HP(CH 2 CH 2 CO 2 −)(CH 2 CH 2 CO 2 H) 2 ≫ +HP(CH 2 CH 2 CO 2 H) 3. This is the first time to decipher the reactivity of all the TCEP protolysis species in the redox reactions of TCEP. Additionally, activation parameters were also measured for the reaction of P(CH 2 CH 2 CO 2 −) 3 with [IrCl 6 ]2− yielding Δ H 5 ‡ = 26.3 ± 1.4 kJ∙mol−1 and Δ S 5 ‡ = −48 ± 5 J∙K−1∙mol−1; a possible mode of electron transfer is discussed. No doubt, the mechanism and the reactivity derived from the present work can serve as a model for the oxidations of TCEP by other single electron oxidants that are involved in chemically- and biologically-important processes. [ABSTRACT FROM AUTHOR]

• 1 g of Tenax is recommended for bioaccessibility determination of triazole fungicides. • Tenax was associated with improved the IVIVC correlation for triazole fungicides. • A negative relationship was found between pesticide bioaccessibility and hydrophobicity. • HQs calculated after the incorporation of Tenax into the RIVM method ranged from 0.2449 to 0.7476. In vitro bioaccessibility assays have been developed for high-throughput prediction of relative bioavailability (RBA). However, methods to reliably and efficiently assess pesticide residues remain limited, hindering the precise estimation of pesticide exposure risk. The inclusion of a sorption sink material to simulate intestinal sorption could be a promising approach to optimize in vitro bioaccessibility methods. The current study aimed to explore the feasibility of incorporating Tenax into the Rijksinstituut voor Volksgezondheid en Milieu (RIVM) method for accurate evaluation of the bioaccessibility of triazole fungicides. The use of 1.0 g of Tenax enabled the valid trapping of triazole fungicides released from grape, resulting in a significant increase of 23.59–38.51 % in the value of bioaccessibility. A strong in vivo – in vitro correlation was observed between pesticide RBA and bioaccessibility, suggesting that the Tenax-assisted RIVM method is a suitable replacement for time-consuming and laborious in vivo alternatives. In addition, the exposure assessment indicated that the hazard quotients for triazole fungicides in grape may be overestimated by 5.79–27.34 % without considering bioaccessibility based on the Tenax-assisted RIVM method. These results provide further insights into the assessment of bioaccessibility-based human exposure to pesticides as well as dietary exposure and related risk for human health. [ABSTRACT FROM AUTHOR]

Amitriptyline (AMI), the most commonly prescribed tricyclic antidepressant, is widely detected in water environments. Exposure to AMI may lead to diverse adverse effects on aquatic organisms, but little is known about the effect of short-term exposure to AMI on the gut microbiota of aquatic organisms and their recovery characteristics. In the present study, adult zebrafish (Danio rerio) were exposed to AMI (0, 2.5, 10, and 40 μg/L) for seven days, and then allowed to recover in AMI-free culture water for 21 days. The exposure caused gut damages in all the AMI treated groups of zebrafish, which became more severe after recovery compared to the control group. AMI exposure also disturbed the microbiota of zebrafish guts and rearing water even after the 21-day recovery period. Furthermore, AMI exposure affected microbes involved in the substance and energy metabolic functions in zebrafish guts and tended to increase the abundance of microbial genera associated with opportunistic pathogens. In addition, the microbial predicted metabolic functions in AMI-exposed guts of zebrafish were significantly altered after the 21-day recovery period, explaining the persistent effects of short-term exposure to AMI. The results of this study suggest that acute exposure to AMI may have persistent impacts on the gut histomorphology and the gut microbiota in aquatic organisms. [Display omitted] • AMI exposure caused gut damages in zebrafish and became more severe after recovery. • AMI exposure disturbed the bacterial communities of zebrafish guts and water. • Persistent impacts of AMI caused dysbiosis in zebrafish gut microbiota. • AMI exposure disordered the metabolic functions of gut microbiota after recovery. [ABSTRACT FROM AUTHOR]

It is believed that chronic inflammation as seen in patients with ulcerative colitis significantly increases the colorectal cancer (CRC) risk and functions as the main driving force for the development of colitis associated CRC. Recently, increasing evidences suggest that inflammation is also involved in the processing of sporadic CRCs that mostly develop from the preformed adenomas through a long-term progression. Within the adenoma/CRC tumor microenvironment, high dense immunocytes with significant phenotypic and functional changes have been observed. These cells might produce high level of inflammatory mediators and then affect the adenoma-cancer transition. In this review, we summarize the update on altered phenotypes and inflammatory mediators within the tumor microenvironment from the adenomatous stage to the cancerous stage, and discuss the significance of inflammatory mediators as biomarkers in predicating the progression from the premalignant adenoma lesion to the sporadic CRC lesion and the potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Background A detailed knowledge about the degradation mechanism of chitosanase hydrolysis is critical for the design of novel enzymes to produce well-defined chito-oligosaccharide products. Methods Through the combination of structural and biochemical analysis, we present new findings that provide novel insights into the degradation mechanism of chitosanase OU01. Results We have determined the crystal structure of Asp 43 /Ala mutant of OU01, and have trapped the hydrolyzed product of the reaction. This structure reveals the role of the general acid (Glu 25 ) in catalysis. Two structural features about the mechanisms of the non-processive chitosanases are described for the first time. 1). Structural comparison reveals that the enzyme goes through an open–closed–open conformational transition upon substrate binding and product release; 2). polar residues constitute the substrate binding cleft. Additional site important for polymeric substrate recognition is identified and a three-step polymeric substrate recognition mechanism is proposed. Conclusions Detailed substrate recognition mechanism is described for non-processive chitosanase for the first time. General significance These findings provide new structural insights into the understanding of overall hydrolysis mechanism for non-processive chitosanase, and also will facilitate the design of new enzymes used for industrial purpose. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that play important roles in the development and functions of the brain. Extensive studies have revealed critical roles for miRNAs in brain development and function. Dysregulation or altered expression of miRNAs is associated with abnormal brain development and pathogenesis of neurodevelopmental diseases. This review serves to highlight the versatile roles of these small RNA molecules in normal brain development and their association with neurodevelopmental disorders, in particular, two closely related neuropsychiatric disorders of neurodevelopmental origin, schizophrenia and bipolar disorder. [ABSTRACT FROM AUTHOR]

The dinoflagellate Prorocentrum minimum was successfully detected using loop-mediated isothermal amplification (LAMP) and real-time fluorescence quantitative PCR (RTFQ-PCR). Both specificity and sensitivity testing in the two methods have been validated. In the LAMP assay, the specific ladder-like pattern of bands only appeared in those templates containing P. minimum. The sensitivity of LAMP was tenfold higher than conventional PCR. In RTFQ-PCR assay, only positive amplifications were detected from those samples containing P. minimum. RTFQ-PCR can detect 0.1 cells and 10 pg of DNA within 40 cycles, showing its high sensitivity. Cells could be quantified according to standard curves in agreement with the quantification by standard microscopy counting methods. The LAMP method therefore is appropriate for on-the-spot testing because of its rapidity and simplification, and the RTFQ-PCR is fit for laboratory testing owing to its accurate quantification. The two methods are of significance in forecasting red tides. [ABSTRACT FROM AUTHOR]

Reliable, reproducible, and valid fingerprint analysis methods using high-performance liquid chromatography-photodiode array detection (HPLC-DAD) for characteristic bioactive water-solution extracts ofRadix Isatidis,Folium Isatidis, and their preparations were firstly developed and validated. Ninety-three batches of samples were investigated and the common fingerprinting profile of water-soluble extracts was established with professional analytical software recommended by the State Food and Drug Administration (SFDA). The reference chromatogram was also generated with 24 common peaks showing large peak areas and good separation from adjacent peaks, the total peak areas of 24 common peaks were more than 85% of the total peak areas. Nine chemical components—including cytidine, progoitrin, hypoxanthine, epiprogoitrin, uridine, adenosine, xanthine, gluconapin, and R,S-goitrin—were identified as characteristic peaks. Hierarchical clustering analysis (HCA) and Principal Component Analysis (PCA) were also performed to classify and differentiate the 93 batches of the samples. As a result, data obtained from the two analytical methods showed good consistence with each other in an overall trend. The chromatographic fingerprint methods by HPLC-DAD were very useful in evaluating and controlling the quality ofRadix Isatidis,Folium Isatidis, and their preparations. [ABSTRACT FROM AUTHOR]

Abstract: The core transcriptional regulatory circuitries are important for controlling stem cell self-renewal and differentiation. Nuclear receptors provide an ideal model to regulate gene expression in both ligand-dependent and ligand-independent manners. Recent studies of regulatory events by nuclear receptors in neural stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs) provided unique insights into mechanisms of stem cell regulation and provided invaluable resources for regenerative medicine. Nuclear receptors have been shown to be key players in stem cell self-renewal, pluripotency, and reprogramming. We summarize recent progress of studies on nuclear receptors in stem cell field as well as the potential therapeutic implications of these nuclear receptors and their cognate ligands. These studies not only uncover molecular mechanisms of stem cell regulation, but also provide unique opportunities for drug discovery. [ABSTRACT FROM AUTHOR]

Abstract: Two fundamental properties of stem cells are their ability to self-renew and to differentiate. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Stem cell self-renewal is regulated by the dynamic interplay between transcription factors, epigenetic control, microRNA (miRNA) regulators, and cell-extrinsic signals from the microenvironment in which stem cells reside. Recent progress in defining specific roles for cell-intrinsic factors and extrinsic factors in regulating stem cell self-renewal starts to unfold the multilayered regulatory networks. This review focuses on cell-intrinsic regulators, including orphan nuclear receptor TLX, polycomb transcriptional repressor Bmi1, high-mobility-group DNA binding protein Sox2, basic helix-loop-helix Hes genes, histone modifying enzymes and chromatin remodeling proteins, and small RNA modulators, as well as cell-extrinsic signaling molecules, such as Wnt, Notch, Sonic hedgehog (Shh), TGFα, EGF, and FGF. Unraveling the mechanisms by which neural stem cells renew themselves will provide insights into both basic neurosciences and clinical applications of stem cell-based cell replacement therapies for neurodegenerative diseases. [Copyright &y& Elsevier]

Orphan nuclear receptors provide a unique resource for uncovering novel regulatory systems that impact human health and also provide drug targets for a variety of human diseases. Ligands of nuclear receptors have been used in several important therapeutic areas, such as breast cancers, skin disorders and diabetes. Orphan nuclear receptors, therefore, represent a tremendous opportunity in understanding and treating human diseases. Here, I highlight recent advances in the use of orphan nuclear receptors and their potential as targets for drug discovery in diabetes, obesity, neurodegenerative diseases and other related disorders. [Copyright &y& Elsevier]

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells. [ABSTRACT FROM AUTHOR]

Background: Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. Objectives: To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Design: Cross-sectional study. Methods: The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. Results: The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. Conclusion: This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients. Plain language summary: Therapeutic drug monitoring-based nomogram predicts primary endoscopic response in Crohn's disease The present study established a therapeutic drug monitoring-based nomogram, which exhibits an exceptional predictive value, remarkable accuracy, and discrimination. This algorithmic nomogram holds the potential to enhance clinicians' comprehension of the underlying mechanisms contributing to individual patients' failure in achieving expected efficacy. Such approach is crucial for optimizing therapy options and facilitating biologic switching in refractory Crohn's disease. [ABSTRACT FROM AUTHOR]

The importance of glial cells, mainly astrocytes, oligodendrocytes, and microglia, in the central nervous system (CNS) has been increasingly appreciated. Recent advances have demonstrated the diversity of glial cells and their contribution to human CNS development, normal CNS functions, and disease progression. The uniqueness of human glial cells is also supported by multiple lines of evidence. With the discovery of induced pluripotent stem cells (iPSCs) and the progress of generating glial cells from human iPSCs, there are numerous studies to model CNS diseases using human iPSC-derived glial cells. Here we summarize the basic characteristics of glial cells, with the focus on their classical functions, heterogeneity, and uniqueness in human species. We further review the findings from recent studies that use iPSC-derived glial cells for CNS disease modeling. We conclude with promises and future directions of using iPSC-derived glial cells for CNS disease modeling. • Glial cell heterogeneity and species specificity • iPSC-derived astrocytes in neurological diseases • iPSC-derived oligodendrocytes in neurological diseases • iPSC-derived microglia in neurological diseases [ABSTRACT FROM AUTHOR]

As our ongoing research project on Ban Lan Gen (Isatis tinctoria roots), a total of 23 alkaloids were obtained. Compounds 1 and 2 contain an unusual C–C bond between the 2(1H)-quinolinone moiety and the phenol moiety and between the 2(1H)-quinolinone moiety and the 1H-indole moiety, respectively. Compound 3 possesses an unusual carbon skeleton and its putative biosynthetic pathway was discussed, and Compound 23 was deduced as a new indole alkaloid glycoside. Compounds 4–7 were identified as four new natural products by extensive spectroscopic experiments. Additionally, the anti-inflammatory activity was assessed based on nitric oxide (NO) production using Lipopolysaccharide-stimulated RAW264.7 macrophages. Compounds 9, 15, and 17 showed inhibitory effects with IC50 values of 1.2, 5.0, and 74.4 μM. [ABSTRACT FROM AUTHOR]

Five pairs of alkaloid enantiomers (1a/1b–5a/5b) were obtained from Isatis indigotica (I. indigotica) roots. Among them, 1a/1b, 2a/2b and 3a/3b were determined as three pairs of new alkaloid enantiomers. Their structures were elucidated by physicochemical properties and spectroscopic methods. The absolute configurations were deduced by comparison of their experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra, as well as by single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation. Alkaloids 1a and 1b possess an unpresented carbon skeleton and their putative biosynthetic pathways are discussed. Moreover, all of the alkaloids were tested for their nitric oxide (NO) inhibitory effects in RAW 264.7 cells, and 4a and 4b showed inhibitory effects with IC50 values of 76.97 μM and 65.88 μM, respectively. [ABSTRACT FROM AUTHOR]

Stabilizing LiCoO2 (LCO) at 4.5 V rather than the common 4.2 V is important for the high specific capacity. In this study, we developed a simple and efficient way to improve the stability of LiCoO2 at high voltages. After a simple sol–gel method, we introduced trifluoroacetic acid (TA) to the surface of LCO via an afterwards calcination. Meanwhile, the TA reacted with residual lithium on the surface of LCO, further leading to the formation of uniform LiF nanoshells. The LiF nanoshells could effectively restrict the interfacial side reaction, hinder the transition metal dissolution and thus achieve a stable cathode–electrolyte interface at high working-voltages. As a result, the LCO@LiF demonstrated a much superior cycling stability with a capacity retention ratio of 83.54% after 100 cycles compared with the bare ones (43.3% for capacity retention), as well as high rate performances. Notably, LiF coating layers endow LCO with excellent high-temperature performances and outstanding full-cell performances. This work provides a simple and effective way to prepare stable LCO materials working at a high voltage. [ABSTRACT FROM AUTHOR]

Advanced detection of RNA modifications, especially N 6-methyladenosine, paves the way for transcriptome-wide, single-cell, and stoichiometric modification profiling at single-nucleotide resolution. RNA modification databases, tumor atlases, drug-like compound libraries, and machine learning have accelerated therapeutic development focused on epitranscriptomics. Novel RNA modification engineering tools based on the CRISPR/Cas technology or endogenous RNA modification machinery can be applied to uncover causal relationships between individual modification sites and phenotypic outcomes. The epitranscriptomics field has undergone tremendous growth since the discovery that the RNA N 6-methyladenosine (m6A) modification is reversible and is distributed throughout the transcriptome. Efforts to map RNA modifications transcriptome-wide and reshape the epitranscriptome in disease settings have facilitated mechanistic understanding and drug discovery in the field. In this review we discuss recent advancements in RNA modification detection methods and consider how these developments can be applied to gain novel insights into the epitranscriptome. We also highlight drug discovery efforts aimed at developing epitranscriptomic therapeutics for cancer and other diseases. Finally, we consider engineering of the epitranscriptome as an emerging direction to investigate RNA modifications and their causal effects on RNA processing at high specificity. [ABSTRACT FROM AUTHOR]

To clarify the residue formation of prothioconazole and its main metabolite in wheat plants, the uptake, translocation, and metabolism of prothioconazole in wheat roots and leaves were investigated by nutrient solution culture and the spraying method. The results showed that prothioconazole and its metabolites showed a trend of increasing and then decreasing in wheat plants under two treatment methods, and the concentration of prothioconazole and its metabolites was higher in the high-concentration group (5000 μg/mL) than in the low-concentration group (1000 μg/mL). The transferability from stem to leaf was stronger than that from root to stem. In the nutrient solution culture, prothioconazole and its metabolites were mainly enriched in wheat roots. The concentration of prothioconazole in wheat roots increases with the increase in prothioconazole concentration and was significantly higher than the prothioconazole concentration on stems and leaves. In wheat leaves in the spraying method, prothioconazole and its metabolites were conducted from leaves to stems and roots up to the nutrient solution. Prothioconazole-desthio was detectable in wheat nutrient solution, while prothioconazole was not detected. Analysis of actual samples of 9 wheat grains and 28 flours showed that the residues of prothioconazole and its metabolites met the maximum residue limit (0.1 mg/mL) set in China and by the Codex Alimentarius Commission. The results will provide a theoretical basis for the scientific use of prothioconazole and food security assurance. [ABSTRACT FROM AUTHOR]

As chemical drugs, separation and quantification of the specific enantiomer from the chiral compounds in herbal medicines are becoming more important. To clarify the chemical characterization of chiral glucosinolates—the antiviral active ingredients of Radix Isatidis, an optimized efficient method of HPLC-UV-CD was developed to simultaneously separate and quantify the four main chiral glucosinolates: progoitrin, epiprogoitrin, and R,S-goitrin. The first step was to determine progoitrin, epiprogoitrin, and R,S-goitrin using HPLC-UV, and then determine the R-goitrin and S-goitrin by coupling with CD detection. Subsequently, through the linear relations between anisotropy factor (g factor) and the percent optical purity of R-goitrin, the contents of R-goitrin and S-goitrin from the R,S-goitrin mixture were calculated separately. Furthermore, the chemical composition features of the four chiral glucosinolates in 37 samples from crude drugs, decoction pieces, and granules of R. Isatidis were conducted. The total content of the four glucosinolates was obviously higher in crude drugs, and the variance character of each glucosinolate contents was different. In summary, the accurate measurement method reported here allows for better control of the internal quality of R. Isatidis and its granules and provides a powerful approach for the analysis of other chiral components in traditional Chinese medicines. [ABSTRACT FROM AUTHOR]

Endotoxic shock exhibits a considerably high mortality risk. It is defined as a systemic inflammatory response syndrome caused by a microbial infection. Radix Isatidis has anti-inflammatory, antiviral, and antipyretic effects and is used worldwide. This study investigated the antiendotoxin sepsis effects of an aqueous R. Isatidis extract (RIE) and explored the possible pharmacological molecular mechanisms. Male C57BL/6J mice were intravenously injected with 15 mg/kg lipopolysaccharide (LPS) to induce endotoxic shock. The results demonstrated that the survival rate of mice pretreated with RIE increased, and LPS-induced liver and lung damage were reduced by inhibiting inflammation. For elucidating detailed molecular mechanisms, we focused on LPS-induced transcription factors: nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3). Our results demonstrated that the protective effects of RIE were strongly dependent on IRF3-induced interferon-β, not on NF-κB-induced tumor necrosis factor-α and interleukin-1β. In addition, RIE suppressed the phosphorylation of IRF3, not NF-κB. In conclusion, this study revealed the antiendotoxic properties of RIE on LPS-induced sepsis and provided mechanistic evidence for the beneficial effects of RIE. [ABSTRACT FROM AUTHOR]

Background: α-fetoprotein (AFP) response has been demonstrated as a biomarker for unresectable hepatocellular carcinoma (uHCC) patients receiving immunotherapy, but its definition is still unclear. This exploratory study investigated the AFP trajectory and clinical outcomes of receiving atezolizumab plus bevacizumab (Atez/Bev) therapy. Methods: This secondary analysis used the Atez/Bev arm data of phase III IMbrave150 study to distinguish potential AFP changing rate trajectories through latent class trajectory models. The multivariable Cox models were applied to calculate adjusted hazard ratios (HRs) and 95% CIs for clinical outcomes. Results: Three distinct trajectories were identified among the uHCC patients with 7 times (range, 3 to 28) of AFP measurements: low-stable (50.0%, n = 132), sharp-falling (13.3%, n = 35), and high-rising (36.7%, n = 97). Compared with the high-rising class, HRs of disease progression were 0.52 (95% CI: 0.39, 0.70) and 0.26 (95% CI: 0.16, 0.43) for the low-stable class and sharp-falling class, respectively. In contrast, HRs of death were 0.59 (95% CI: 0.40, 0.81) and 0.30 (95% CI: 0.16, 0.57) for the two groups after propensity score adjustment. Besides, AFP trajectories had the highest relative importance of each covariate to survival. Discussion: There are three distinct AFP trajectories in uHCC patients receiving Atez/Bev, and it is an independent biomarker for clinical outcomes. [ABSTRACT FROM AUTHOR]

Demyelinating disorders are among the most common and debilitating diseases in neurology. Canavan disease (CD) is a lethal demyelinating disease caused by mutation of the aspartoacylase (ASPA) gene, which leads to the accumulation of its substrate N‐acetyl‐l‐aspartate (NAA), and consequently demyelination and vacuolation in the brain. In this study, hypoimmunogenic human induced pluripotent stem cell (iPSC)‐derived oligodendrocyte progenitor cells (OPC) are developed from a healthy donor as an "off‐the‐shelf" cell therapy. Hypoimmunogenic iPSCs are generated through CRISPR/Cas9 editing of the human leukocyte antigen (HLA) molecules in healthy donor‐derived iPSCs and differentiated into OPCs. The OPCs are engrafted into the brains of CD (nur7) mice and exhibit widespread distribution in the brain. The engrafted OPCs mature into oligodendrocytes that express the endogenous wildtype ASPA gene. Consequently, the transplanted mice exhibit elevated human ASPA expression and enzymatic activity and reduced NAA level in the brain. The transplanted OPCs are able to rescue major pathological features of CD, including defective myelination, extensive vacuolation, and motor function deficits. Moreover, the hypoimmunogenic OPCs exhibit low immunogenicity both in vitro and in vivo. The hypoimmunogenic OPCs can be used as "off‐the‐shelf" universal donor cells to treat various CD patients and many other demyelinating disorders, especially autoimmune demyelinating diseases, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]

Alginate lyases have a wide range of industrial applications, such as oligosaccharide preparation, medical treatment, and bioconversion. Therefore, the discovery and characterization of novel alginate lyases are extremely important. PL-6 alginate lyases are classified into two groups: those with a single domain or two domains. However, only one structure of a two-domain alginate lyase has been determined to date. In this study, we characterized a novel single-domain PL-6 alginate lyase (named AlyF). According to the biochemical analysis, AlyF possesses unique features compared with other PL-6 enzymes, including (1) a Ca2+-independent catalytic mechanism and (2) a PolyG-specific cleavage specificity that predominantly produces trisaccharides. The structures of AlyF and its complexes described here reveal the structural basis for these unique features and substrate binding mechanisms, which were further confirmed using mutagenesis. More importantly, we determined the possible subsites specifying the predominantly trisaccharide products of AlyF, which may facilitate the rational design of AlyF for potential applications in preparing a single alginate oligomer. • A novel Ca2+-independent PL-6 alginate lyase, AlyF, was characterized. • The first structure of a single-domain PL-6 alginate lyase was solved. • Instead of Ca2+, a water involved in the catalytic mechanism of AlyF. • The possible subsite responsible for the product distribution was identified by structure-based rational design. [ABSTRACT FROM AUTHOR]

• Female sexual dysfunction is one of the most common symptoms in aging women. • The relationship between serum androgen levels and female sexual dysfunction is controversial. • Liquid chromatography mass spectrometry is the best way to assess serum androgens. • The intensity of climacteric symptoms significantly affects women's sexual function. • A low education level was found to be a risk factor for female sexual dysfunction in China. The aim of this study was to investigate the factors affecting the sex lives of postmenopausal Chinese women, especially the influence of body weight, climacteric symptoms and androgens. A total of 437 postmenopausal women were investigated in the Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University and two allied medical institutions from April 2020 to March 2021. Sociodemographic data were collected. Female sexual dysfunction was evaluated using the Female Sexual Function Index (FSFI). The modified Kupperman index was used to assess climacteric symptoms. Methods based on liquid chromatography-tandem mass spectrometry were employed to measure the serum levels of total testosterone, bioavailable testosterone, free testosterone, androstenedione and dehydroepiandrosterone. Pearson's correlation coefficient and multiple linear regression analyses were performed to determine the correlation between characteristics and FSFI scores. The multivariate linear regression analysis revealed that the modified Kupperman index score and the factor unsatisfactory marital relations had the strongest negative correlations with all FSFI domains (P < 0.05); secondary education level was negatively associated with desire, arousal and orgasm (P < 0.05). Total testosterone positively affected the score for pain (P < 0.05). There was no correlation between bioavailable testosterone, free testosterone, androstenedione and dehydroepiandrosterone and all FSFI domains (P > 0.05). Climacteric symptoms and sociodemographic factors had a notable effect on sexual function. It is necessary to provide more attention to and intervention for their climacteric symptoms to improve the quality of life of postmenopausal women. [ABSTRACT FROM AUTHOR]

Two-dimensional (2D) ZnS-SnS 2 porous nanosheets are designed as clean and low cost photocatalysts for water splitting. The composites successfully combine high photoelectron reduction potential of ZnS with the sufficient sunlight harvesting ability of SnS 2 . Moreover, SnS 2 acts as an effective electron transfer medium from ZnS to SnS 2 due to the construction of quasi-type II structure. This greatly promotes the transfer of electron-hole pairs and effectively inhibits their recombination. Especially, the unique porous nanosheets structure maintains them high specific surface area and countless reactive sites, which increases the reactants' contact area and facilitates the migration of carriers upon photocatalysis. This further suppresses the charge recombination and improves the photocatalysts' stability. As a result, an optimized specific surface area of 246.7 m 2  g −1 and photocatalytic H 2 generation rate of 536 μmol h −1 g −1 are achieved in the absence of a surfactant and co-catalyst, which is 10 times higher than ZnS and 17 times higher than SnS 2 . In addition, the porous nanosheets have fairly good photocatalytic stability and can be reused at least five cycles without obvious changes in activity and structure. This work successfully presents the potential of ZnS and SnS 2 -based photocatalyst for clean and low cost hydrogen production from water splitting. [ABSTRACT FROM AUTHOR]

Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system. [ABSTRACT FROM AUTHOR]

A full-scale field investigation studying the emission of trace elements was carried out at a coal-fired power plant equipped with a wet flue gas desulfurization (WFGD) system and an electrostatic-fabric-integrated precipitator (EFIP). The results indicated that 76%–94% of the As, Pb and Cr are present in the fly ash, and that Hg is distributed in the gypsum and fly ash. The concentrations of As, Pb, Cr and Hg in the electrostatic precipitation ash are 2–4 times higher than what was present in the fabric filtration ash. The results indicated that 2.73% of the As and 4.69% of the Hg are released after the FGD system. The Pb and Cr content in the post-FGD flue gas were identified as extremely low. The BCR leaching results indicated that fly ash with a smaller particle size will release more As. Therefore, fly ash collected by fabric filtration should be regarded as serious concern, and treated seriously. The proportion of Pb in the non-mobile fraction increased with particle size, and a larger portion of Pb was present in the oxidizable fraction as compared to As and Cr. Trace element concentrations in the EFIP under low load (75% load) were measured 3%–25% higher than under the full load. The trace element concentrations in the WFGD decreased with the decreased load. [ABSTRACT FROM AUTHOR]

Septic shock is defined as a subset of sepsis, which is associated with a considerably high mortality risk. The caspase-11 non-canonical inflammasome is sensed and activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis, it plays a critical role in septic shock. However, there are few known drugs that can control caspase-11 non-canonical inflammasome activation. We report here that goitrin, an alkaloid from Radix Isatidis, shows protective effects in LPS-induced septic shock and significant inhibitory effect in caspase-11 non-canonical inflammasome pathway. Male C57BL/6J were injected intraperitoneally with LPS (20 mg/kg) to induce experimental septic shock. The results demonstrated that the survival rates of mice pretreated with goitrin or Toll-like receptor 4 (TLR4) inhibitor TKA-242 increased, and LPS-induced hypothermia and lung damage improved by inhibiting inflammatory response. Elucidating the detailed mechanism, we surprisingly found goitrin is really different from TAK-242, it independent of the TLR4 signal activation, but significantly inhibited the activation of caspase-11 non-canonical inflammasome, including cleaved caspase-11 and N-terminal fragment of gasdermin D (GSDMD-NT). Furthermore, with a nonlethal dose of the TLR3 agonist poly(I:C)-primed and subsequently challenged with LPS to induce caspase-11-mediated lethal septic shock, the efficacy of goitrin had been verified. Those results revealed the effect of goitrin in protective against LPS-induced septic shock via inhibiting caspase-11 non-canonical inflammasome, which provided a new therapeutic strategy for clinical treatment of septic shock. [ABSTRACT FROM AUTHOR]

To investigate the prospective role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in evaluating terminal ileal Crohn's disease (CD) inflammation quantitatively, compared with quantitative dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) and ileocolonoscopic segmental score. Fifty CD patients underwent magnetic resonance enterography (MRE) including IVIM-DWI and quantitative DCE-MRI from Jan. 2017 to Nov. 2019. ADC, D, D* and f value of IVIM-DWI and Ktrans, Kep, and Ve value of DCE-MRI in normal (n = 50) and inflamed bowel segments (n = 50), defined during the clinical MRI analysis, were calculated and compared using Wilcoxon signed-rank tests respectively. Receiver operating characteristic (ROC) analysis was performed. Correlations between IVIM-DWI and DCE-MRI parameters in comparison with ileocolonoscopic segmental score were assessed using Spearman's rank correlation analysis. For IVIM-DWI, ADC, D, D* and f value showed significant differences respectively between normal and inflamed bowel segments (p < 0.05). ADC value presented the highest diagnostic accuracy (AUC = 0.813) and sensitivity (92%), and D value presented the highest specificity (84%) for the evaluation of inflamed bowel segments. For DCE-MRI, Ktrans value presented the highest diagnostic accuracy (AUC = 0.835), the highest sensitivity for Kep value (88%) and the highest specificity for Ve value (96%). ADC, f and Ktrans value had high correlations with ileocolonoscopic score respectively (r = −0.739-0.876, p < 0.01). The logarithm of normalized signal intensity/b-values for IVIM-DWI could also indicate directly the evident difference between the normal and inflamed bowel segments of terminal ileal CD. IVIM-DWI will be another promising noninvasive tool to provide precise quantitative-indicators in evaluating inflamed bowel segments of terminal ileal CD with little contrast-agent damage worries. [ABSTRACT FROM AUTHOR]

After two years into the pandemic of the coronavirus disease 2019 (COVID-19), it remains unclear how the host RNA interference (RNAi) pathway and host miRNAs regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and impact the development of COVID-19. In this study, we profiled small RNAs in SARS-CoV-2-infected human ACE2-expressing HEK293T cells and observed dysregulated host small RNA groups, including specific host miRNAs that are altered in response to SARS-CoV-2 infection. By comparing dysregulated miRNAs in different SARS-CoV-2-infected samples, we identified miRNA-210-3p, miRNA-30-5p, and miR-146a/b as key host miRNAs that may be involved in SARS-CoV-2 infection. Furthermore, by comparing virally derived small RNAs (vsmRNAs) in different SARS-CoV-2-infected samples, we observed multiple hot spots in the viral genome that are prone to generating vsmRNAs, and their biogenesis can be dependent on the antiviral isoform of Dicer. Moreover, we investigated the biogenesis of a recently identified SARS-CoV-2 viral miRNA encoded by ORF7a and found that it is differentially expressed in different infected cell lines or in the same cell line with different viral doses. Our results demonstrate the involvement of both host small RNAs and vsmRNAs in SARS-CoV-2 infection and identify these small RNAs as potential targets for anti-COVID-19 therapeutic development. [ABSTRACT FROM AUTHOR]

• Thimerosal (THI) reduced activity and anxiety in male zebrafish but not in females. • THI increased social interaction in males but decreased it in females. • THI decreased the 5-HT, 5-HIAA, DA, and DOPAC contents in the brain of males. • THI only decreased the DA contents in the brains of females. • THI may alter the behavioral traits of zebrafish by altering their brain monoamines. Thimerosal (THI) is the most widely used form of organic mercury in pharmaceutical and personal care products, and has become a major source of ethylmercury pollution in aquatic ecosystems. However, knowledge about its potential risk to aquatic species is limited. In this study, zebrafish were exposed to THI for 7 days, and variations in their behavioral traits, brain monoaminergic neurotransmitter contents, and related gene expression were investigated. After the 7-day exposure, THI reduced locomotor activity and thigmotaxis in males but not females. Exposure to THI increased the social interaction between females but decreased that between males. The THI exposure also significantly reduced the serotonin (5-HT), 5-hydroxyindoleacetic acid, dopamine (DA), and 3,4-dihydroxyphenylacetic acid contents in the brain of males, but only significantly decreased the DA content in females. Correlation analysis revealed that the neurochemical alterations in the brain of zebrafish play critical roles in the behavioral abnormalities induced by THI exposure. Moreover, THI also significantly altered the expression of some genes associated with the synthesis, metabolism, and receptor binding of 5-HT and DA in the brain of zebrafish. The differences in these gene expressions between female and male zebrafish exposed to THI seem to be an important mechanism underlying their sex-specific responses to this chemical. This is the first report on the sex-specific effects of THI on behaviors and brain monoaminergic neurotransmitter contents in zebrafish, which can further improve our understanding of its toxic effects on teleost. [ABSTRACT FROM AUTHOR]

Adverse health outcomes due to the inhalation of pesticide residues in atmospheric particulate matter (PM) are gaining global attention. Quantitative health risk assessments of pesticide inhalation exposure highlight the need to understand the bioaccessibility of pesticide residues. Herein, the inhalation bioaccessibility of imidacloprid in PM was determined using three commonly used in vitro lung modeling methods (Artificial Lysosomal Fluid, Gamble Solution, and Simulated Lung Fluid). To validate its feasibility and effectiveness, we evaluated the bioavailability of imidacloprid using a mouse nasal instillation assay. The in vitro inhalation bioaccessibility of imidacloprid was extracted using Gamble Solution with a solid–liquid ratio of 1/1000, an oscillation rate of 150 r/min, and an extraction time of 24 h, showed a strong linear correlation with its in vivo liver-based bioavailability (R2 =0.8928). Moreover, the margin of exposure was incorporated into the inhalation exposure risk assessment, considering both formulations and nozzles. The inhalation unit exposure of imidacloprid for residents was 0.95–4.09 ng/m3. The margin of exposure for imidacloprid was determined to be acceptable when considering inhalation bioaccessibility. Taken together, these results indicate that the inhalation bioaccessibility of pesticides should be incorporated into assessments of human health risks posed by PM particles. [Display omitted] • In vitro inhalation bioaccessibility of imidacloprid in PM was established firstly. • The feasibility of in vitro method was validated based on IVIVC model. • The inhalation unit exposures of imidacloprid for residents was 0.95–4.09 ng/m3. • MOE calculated after the incorporation of inhalation bioaccessibility was acceptable. [ABSTRACT FROM AUTHOR]

Pseudouridine (Ψ) is the most abundant post-transcriptional RNA modification and is widespread in multiple RNA species. Ψ impacts various aspects of RNA biology, conferring distinct structural and functional properties to the RNA molecules that it decorates. However, aberrant pseudouridylation contributes to a variety of human diseases, including cancer and genetic disorders. Dysregulation of the Ψ epitranscriptome can arise from mutations and abnormal expression of pseudouridylation machinery, impacting protein translation and other cellular processes. With advancing understanding of Ψ roles in health and disease, efforts are now invested in developing therapeutic and diagnostic approaches targeting Ψ. Emerging reports indicate that Ψ and its installation machinery could be potential pharmacological targets for therapeutic development and may serve as biomarkers for human diseases. Pseudouridine (Ψ) is the most common post-transcriptional RNA modification that is dynamically deposited throughout the transcriptome. RNA pseudouridylation can influence various cellular processes, such as translation and response to environmental stress, and becomes dysregulated in disease. Mutations in Ψ synthases lead to aberrant pseudouridylation of their RNA targets and contribute to cancer progression and genetic disease. The level of excreted Ψ and the expression profile of pseudouridylation machinery may have diagnostic and prognostic value as biomarkers for cancer. The dynamic Ψ epitranscriptome is a potential target for therapeutic development. [ABSTRACT FROM AUTHOR]

• Short-term AMI exposure induced persistent behavioral abnormality in zebrafish. • Short-term AMI exposure induced long-term impacts on brain neurotransmitter levels. • Pathways related to circadian rhythm and axonal regeneration were dysregulated. • Twelve DEGs were predicted as key driver genes in response to the AMI exposure. • Brain 5-HT level may serve as a critical modulator of the persistent AMI pathogenesis. Discontinuation of amitriptyline (AMI) has been demonstrated to induce long-term withdrawal syndromes in mammals. However, no studies have focused on the persistent impacts of short-term AMI exposure on teleosts. Here, following exposure to AMI (2.5 and 40 μg/L) for 7 days (E7), zebrafish were transferred into AMI-free water to recover for 21 days (R21). The behavior, brain neurotransmitters, and brain transcriptional profiles were investigated on E7 and R21. AMI exposure induced persistent hypoactivity (2.5 and 40 μg/L) and abnormal schooling behavior (40 μg/L). AMI also induced long-term impacts on the brain serotonin (5-HT), 5-hydroxyindoleacetic acid, norepinephrine, and acetylcholine levels, several of which showed significant correlations with the locomotor activity or schooling behavior. Transcriptional analysis revealed persistent dysregulation in the pathways involved in the circadian rhythm, glycan biosynthesis and metabolism, and axon guidance in brain samples. Twelve genes were predicted as key driver genes in response to AMI exposure, and their significantly differential expression may direct changes across the related molecular networks. Moreover, upregulated brain 5-HT may serve as the central modulator of the persistent AMI pathogenesis in zebrafish. Considering AMI residues in natural waters may temporarily exceed μg/L, corresponding persistent adverse effects on teleosts should not be ignored. [ABSTRACT FROM AUTHOR]

Diazepam (DZP) residue has been frequently detected in wastewater, surface water, and groundwater due to its extensive use over the decades. In this study, we exposed female Japanese medaka (Oryzias latipes) to environmentally relevant doses of DZP (800 and 8000 ng/L) for 4 weeks, aimed to investigate their behavioral responses and possible links with ocular and brain oxidative stress homeostasis. As a result, DZP exposure could significantly reduce swimming activity (800 ng/L) and anxiety (800 and 8000 ng/L), indicating a sedative effect on medaka. The DZP exposure also significantly increased the social interaction in medaka at 8000 ng/L. Furthermore, exposure to DZP could alter the ocular and brain oxidative stress homeostasis in medaka. The ocular CAT activities significantly increased in the 800 ng/L-DZP groups, and the brain SOD, CAT, GST and MDA levels also significantly increased in both DZP exposure groups. Correlation analysis revealed that the ocular and brain oxidative stress induced by DZP exposure might play an important role in their behavioral toxicity to medaka. Our findings highlight the necessity to clarify the exact link between DZP exposure-induced oxidative stress in the neural and sensor systems and its behavioral toxicity to better assess the risks on nontarget aquatic species. [Display omitted] • Diazepam (DZP) significantly reduced swimming activity in medaka at 800 ng/L. • DZP exposure significantly reduced anxiety in medaka at 800 and 8000 ng/L. • DZP exposure significantly increased social interaction in medaka at 8000 ng/L. • DZP altered the ocular and brain oxidative stress homeostasis in medaka. • Ocular and brain oxidative stress was associated with behavioral toxicity of DZP. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti‐AD drugs in the past decades. However, all drug development programs for disease‐modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)‐derived 3D brain organoids. Because the blood–brain barrier (BBB) leakage is a well‐known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum‐exposed brain organoids are able to recapitulate AD‐like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule‐associated tau protein (p‐Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p‐Tau levels through inducing beta‐secretase 1 (BACE) and glycogen synthase kinase‐3 alpha / beta (GSK3α/β) levels, respectively. In addition, single‐cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid‐based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future. [ABSTRACT FROM AUTHOR]

The transcriptome of SARS-CoV-2-infected cells that reflects the interplay between host and virus has provided valuable insights into mechanisms underlying SARS-CoV-2 infection and COVID-19 disease progression. In this study, we show that SARS-CoV-2 can establish a robust infection in HEK293T cells that overexpress human angiotensin-converting enzyme 2 (hACE2) without triggering significant host immune response. Instead, endoplasmic reticulum stress and unfolded protein response-related pathways are predominantly activated. By comparing our data with published transcriptome of SARS-CoV-2 infection in other cell lines, we found that the expression level of hACE2 directly correlates with the viral load in infected cells but not with the scale of immune responses. Only cells that express high level of endogenous hACE2 exhibit an extensive immune attack even with a low viral load. Therefore, the infection route may be critical for the extent of the immune response, thus the severity of COVID-19 disease status. [ABSTRACT FROM AUTHOR]