Lessons for future pandemics: Temporal evolution and rural-urban variations in the impacts of the COVID-19 on opioid use treatment.

The COVID-19 pandemic introduced imminent and lasting impacts on the opioid crisis in the U.S., including a significant increase in opioid overdose and deaths and in use of telehealth in treatment. What lessons can we learn from the treatment transition during the pandemic that could help tackle the opioid crisis when future pandemics strike? In this paper, we conducted a phone survey with opioid treatment facilities in Pennsylvania to examine the COVID-19's impacts on treatment facilities and individuals with opioid use disorder during the first year of the pandemic. We separated the lockdown period (Mid-March through Mid-May, 2020) from the reopening period that followed, and urban areas from rural areas, to explore temporal evolution and rural-urban variations in the COVID-19's impacts. We found rural-urban heterogeneity in facilities' adoption of telehealth in treatment and in challenges and risk factors faced by their clients during the lockdown period. During the reopening, telehealth was adopted by most facilities, and telehealth-related challenges became less salient; however, both rural and urban facilities reported higher relapse risks faced by their clients, citing factors more likely to be at clients' end and related to socioeconomic stressors and mental health. Our results highlight the vitality of addressing socioeconomic and mental health challenges faced by individuals with OUD, via government policies and community interventions, when future pandemics strike. The findings also indicate the importance of maintaining facilities' financial well-being to provide treatment services.

Global, regional, and national burden of bullying related mental disorders of adolescent from 1990 to 2019: A systematic analysis for the Global Burden of Disease Study 2019.

Few studies have assessed the burden of mental disorders in adolescents related to bullying victimization at the global, regional, and national levels. We analyzed adolescent mental disorder disability-adjusted life years (DALYs) attributed to bullying in 204 countries, following the Global Burden of Disease study 2019 framework. The DALYs rate of adolescent for bullying-related mental disorders global increased from 110.45 (95 % uncertainty intervals (UI): 40.76, 218.62) per 100,000 in 1990 to 138.92 (95 % UI: 54.37, 268.19) per 100,000 in 2019. The largest increase in DALYs rates were obvious in low-SDI and high-SDI regions. In 2019, the DALYs rate of adolescents with bullying-related anxiety disorders was 1.4 times higher than those depressive disorders; the DALYs rate of adolescents with bullying-related mental disorder in females was 1.3 times higher than that of male, and older adolescent (15-19 years old) was 1.4 times higher than younger adolescent (10-14 years old). High-income North America had the fastest increase in DALYs rates of mental disorders related to bullying. In general, a positive correlation was observed between bullying DALY rate of adolescent and SDIs at the regional and national levels. Our study highlights significant disparities in adolescent mental health burden from bullying. Governments must implement adaptive policies to address diverse needs effectively.

Synergic treatment of domestic wastewater and food waste in an anaerobic membrane bioreactor demo plant: Process performance, energy consumption, and greenhouse gas emissions.

Ambient operation and large-scale demonstration have limited the implementation and evaluation of anaerobic membrane bioreactors (AnMBRs) for low-strength wastewater treatment. Here, we studied these issues at an AnMBR demo plant that treats domestic wastewater and food waste together at ambient temperatures (7-28 °C). At varied hydraulic retention times (HRTs, 8-42 h), the AnMBR achieved a COD removal efficiency and biogas production of 80.4% ± 3.9% and 66.5 ± 9.4 NL/m3-Influent, respectively. Moreover, a stable high membrane flux of 14.4 L/m2/h was reached. The electric energy consumption for the AnMBR operation was 0.269-0.433 kW·h/m3, and 49.4%-91.3% could be compensated by the electric energy produced from methane production. At an HRT of 10 h, the AnMBR system demonstrated an impressively low net electric energy consumption of merely 0.05 kW·h/m3, resulting in a net greenhouse gas emission of 0.015 CO2-eq/m3, cutting 85% compared to the conventional activated sludge process. Achievements in this study provide key parameters for the ambient operation of AnMBR and demonstrate that AnMBR is an energy-saving and low-carbon solution for low-strength wastewater treatment.

The SPARC-related modular calcium binding 1 (Smoc1) regulated by androgen is required for mouse gubernaculum development and testicular descent.

ABSTRACT: Testicular descent occurs in two consecutive stages: the transabdominal stage and the inguinoscrotal stage. Androgens play a crucial role in the second stage by influencing the development of the gubernaculum, a structure that pulls the testis into the scrotum. However, the mechanisms of androgen actions underlying many of the processes associated with gubernaculum development have not been fully elucidated. To identify the androgen-regulated genes, we conducted large-scale gene expression analyses on the gubernaculum harvested from luteinizing hormone/choriogonadotropin receptor knockout (Lhcgr KO) mice, an animal model of inguinoscrotal testis maldescent resulting from androgen deficiency. We found that the expression of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (Smoc1) was the most severely suppressed at both the transcript and protein levels, while its expression was the most dramatically induced by testosterone administration in the gubernacula of Lhcgr KO mice. The upregulation of Smoc1 expression by testosterone was curtailed by the addition of an androgen receptor antagonist, flutamide. In addition, in vitro studies demonstrated that SMOC1 modestly but significantly promoted the proliferation of gubernacular cells. In the cultures of myogenic differentiation medium, both testosterone and SMOC1 enhanced the expression of myogenic regulatory factors such as paired box 7 (Pax7) and myogenic factor 5 (Myf5). After short-interfering RNA-mediated knocking down of Smoc1, the expression of Pax7 and Myf5 diminished, and testosterone alone did not recover, but additional SMOC1 did. These observations indicate that SMOC1 is pivotal in mediating androgen action to regulate gubernaculum development during inguinoscrotal testicular descent.

Genome-wide association analysis to search for new loci associated with stroke risk in Northwestern Chinese population.

BACKGROUND AND PURPOSE: Genetic factors play an important role in the pathogenesis of stroke(S). This study aimed to screen the loci associated with S risk in northwestern Chinese population by genome-wide association analysis (GWAS). METHODS: A total of 1394 subjects, including 682 S patients and 692 controls, were enrolled in this study. SPSS 25.0 software was used for statistical analysis, and the independent sample t-test as well as Chi-square test were used to analyze the differences in age and gender between the case and control groups. The Precision Medicine Diversity Array (PMDA) genotyping chip was used in this study. The genotyping platform was the Gene Titan multi-channel instrument, and the Axiom Analysis Suite 6.0 software was used for the data analyzing. Besides, the LASSO analysis, SNP-SNP and GO/KEGG analysis were conducted to analyze the association between significant loci and S risk. RESULTS: A total of 30 SNPs were found to be associated with the S risk based on additive model (p < 5 × 10-8). After the LASSO screening, 22 SNPs showed the diagnostic value in S. The SNPs interaction analysis further screened the SNP-SNP interaction groups associated with the S risk(p < 0.05). Finally, the GO/KEGG analysis discovered the suggestive significance loci could be involved in the S development mainly by immune-related functions and pathways. CONCLUSION: This study discovered 30 S related SNPs and analyzed the potential pathways associated with genes located on the 30 SNPs, which were beneficial for enriching the genetic mechanism analysis of S in northwestern Chinese population.

A Dual-Modality Home-Based Cardiac Rehabilitation Program for Adults with Cardiovascular Disease: Single-Arm Remote Clinical Trial.

BACKGROUND: Cardiac rehabilitation (CR) is a safe and effective intervention for individuals with cardiovascular disease (CVD). However, the majority of eligible patients do not complete CR. Growing evidence suggests that home-based CR (HBCR) programs are comparable in effectiveness and safety to traditional center-based programs. More research is needed to explore different ways to deliver HBCR programs to CVD patients. OBJECTIVE: This study aims to assess the feasibility and impact of a digital HBCR program (RecoveryPlus.Health, RPH-D) that integrates both telehealth and mHealth modalities on functional exercise capacity, resting heart rate, and quality of life among adults with cardiovascular disease (CVD). METHODS: This 12-week prospective, single-arm remote clinical trial used a within-subject design. We recruited adults with CVD (age 40+) from the community with a CR-eligible diagnosis (stable angina pectoris, myocardial infarction, heart failure, etc.) between May and August of 2023. All enrolled patients referred to the RPH clinic in Roanoke, TX were included. The care team provided guideline-concordant CR services to study participants via two modalities: 1) a synchronous telehealth exercise training via video conferencing; and 2) an asynchronous mHealth virtual coaching App (RPH App). Baseline intake survey, electronic health record (EHR), and app log data were used to extract individual characteristics, care processes, and telehealth/mHealth engagement data. Feasibility was measured by program completion rate and CR services use. Efficacy was measured by changes in 6-minute walk test (6MWT), resting heart rate, and quality of life (SF-12) before and after the 12-week program. Paired t tests were used to examine the changes in the outcome variables pre-post intervention. RESULTS: A total of 162 met the inclusion criteria, 75 (46.3%) consented and were enrolled. The participants' average age was 64.24 (SD 10.30) years; 37 (49%) were male, and 46 (61%) were White. Heart failure was the most common diagnosis (49%). A total of 62 (83%) participants completed the 12-week study, 62 (83%) used the telehealth modality with an average of 9.63 (SD 3.33) sessions completed, and 59 (79%) used the mHealth modality with an average of 10.97 (SD 11.70) sessions completed. Post intervention, 50 (81%) participants had improved 6MWT, with an average improvement of 40.0 meters (95% CI, 25.6 to 57.1). The average SF-12 physical and mental summary scores improved by 2.7 points (95% CI, 1.1 to 4.3) and 2.2 points (95% CI, 0.1 to 4.5), respectively. There were no changes in resting heart rate and no exercise-related adverse events were reported. CONCLUSIONS: The RecoveryPlus.Health digital HBCR program showed feasibility and efficacy in a group of nationally recruited CVD patients. The findings add to the evidence that a telehealth and mHealth dual-modality HBCR program may be a promising approach to overcome some of the main barriers to improving CR access in the U.S. CLINICALTRIAL: ClinicalTrials.gov NCT05804500.

SERPINH1 modulates apoptosis by inhibiting P62 ubiquitination degradation to promote bone metastasis of prostate cancer.

Prostate cancer (PCa) is one of the most prevalent urogenital malignancies. Bone metastasis from PCa reduces patient survival rates significantly. There currently exists no effective treatment for bone metastatic PCa, and the underlying mechanisms remain unclear. This study performed transcriptomic screening on PCa bone metastasis specimens and intersection analysis in public databases and identified SERPINH1 as a potential target for treatment. SERPINH1 was found to be upregulated in PCa bone metastases and with poor prognosis, high Gleason score, and advanced metastatic status. SERPINH1 induced PCa cells' bone metastasis in vivo, promoted their proliferation, and mitigated apoptosis. Mechanistically, SERPINH1 bound to P62, reducing TRIM21-mediated K63-linked ubiquitination degradation of P62 and promoting proliferation and resistance to apoptosis of PCa. This study suggests the regulation of ubiquitination degradation of P62 by SERPINH1 that promotes PCa bone metastasis and can be considered as a potential target for treatment of bone metastatic PCa.

Cross-modal group-relation optimization for visible-infrared person re-identification.

Visible-infrared person re-identification (VIPR) plays an important role in intelligent transportation systems. Modal discrepancies between visible and infrared images seriously confuse person appearance discrimination, e.g., the similarity of the same class of different modalities is lower than the similarity between different classes of the same modality. Worse still, the modal discrepancies and appearance discrepancies are coupled with each other. The prevailing practice is to disentangle modal and appearance discrepancies, but it usually requires complex decoupling networks. In this paper, rather than disentanglement, we propose to measure and optimize modal discrepancies. We explore a cross-modal group-relation (CMGR) to describe the relationship between the same group of people in two different modalities. The CMGR has great potential in modal invariance because it considers more stable groups rather than individuals, so it is a good measurement for modal discrepancies. Furthermore, we design a group-relation correlation (GRC) loss function based on Pearson correlations to optimize CMGR, which can be easily integrated with the learning of VIPR's appearance features. Consequently, our CMGR model serves as a pivotal constraint to minimize modal discrepancies, operating in a manner similar to a loss function. It is applied solely during the training phase, thereby obviating the need for any execution during the inference phase. Experimental results on two public datasets (i.e., RegDB and SYSU-MM01) demonstrate that our CMGR method is superior to state-of-the-art approaches. In particular, on the RegDB dataset, with the help of CMGR, the rank-1 identification rate has improved by more than 7% compared to the case of not using CMGR.

Association of serum uric acid to serum creatinine ratio with 1-year stroke outcomes in patients with acute ischemic stroke: A multicenter observational cohort study.

BACKGROUND AND PURPOSE: Considering the reliance of serum uric acid (SUA) levels on renal clearance function, its role in stroke outcomes remains controversial. This study investigated the association of renal function-normalized SUA (SUA to serum creatinine ratio, SUA/SCr), a novel renal function index, with the 1-year outcomes in patients with acute ischemic stroke (AIS). METHODS: This is a prospective, multicenter observational study. Renal function-normalized SUA levels were determined by calculating the ratio of SUA to SCr. One-year outcomes included stroke recurrence, all-cause mortality, and poor prognosis. Multivariable Cox regression analyses and restriction cubic splines for curve fitting were used to evaluate SUA/SCr's association with 1-year stroke outcomes. RESULTS: Among 2294 enrolled patients, after adjustment for potential confounders, multivariable Cox regression analyses showed that each one-unit increase in SUA/SCr corresponded to a 19% decrease in 1-year stroke recurrence in patients with AIS. SUA/SCr was analyzed as a continuous variable and categorized into quartiles (Q1-Q4). Compared with the Q1 reference group, Q2, Q3, and Q4 showed significantly lower 1-year stroke recurrence risks. The trend test indicated significant differences in the 1-year stroke recurrence trend from Q1 to Q4. In these patients, SUA/SCr did not show a significant association with poor prognosis or all-cause mortality. Curve fitting revealed SUA/SCr had a negative but nonlinear association with 1-year stroke recurrence. CONCLUSIONS: In patients with AIS, low SUA/SCr may be an independent risk factor for 1-year stroke recurrence. Changes in SUA/SCr had no significant impact on 1-year poor prognosis and all-cause mortality.

Antibiofilm Metabolites from Marine-derived Streptomyces sp. ZS-A31.

A novel compound streptothiomycin F (1), and a new natural product, N-(5-nitropentyl)acetamide (2), were discovered alongside ten previously identified compounds (3-12) through solid fermentation of marine-derived Streptomyces sp. ZS-A31 based on rice. The chemical structures of compounds 1-2 were elucidated using 1D and 2D NMR, as well as HRESIMS data analysis. Evaluation of all isolated compounds for their antibiofilm and antibacterial activities against P. aeruginosa was carried out using microdilution and crystal violet staining methods. Results highlighted the weak potency of the known compounds lumichrome (3) and vanillic acid (7) in inhibiting biofilm formation.

Effect of Short-term Deep Breathing Exercises on Perioperative Anxiety and Pain in Pediatric Orthopedic Patients: A Randomized Controlled Trial.

PURPOSE: There are currently no pediatric studies examining the effects of deep breathing on perioperative pain and anxiety. This study sought to determine the effect of short-term deep breathing exercises on perioperative anxiety and pain in pediatric patients and their parents. DESIGN: A randomized controlled trial was conducted in the Department of Orthopaedic Surgery where pediatric patients about to undergo surgery were allocated to a control group or a deep breathing group. In the intervention group, patients and their main guardian were guided to practice 10 minutes of deep breathing exercises twice a day for 3 to 4 days prior to surgery. Perioperative anxiety and pain were measured for both the children and parents as outcome indicators. METHODS: Perioperative anxiety was measured using the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF) and state anxiety was measured using the State-Trait Anxiety Inventory (STAI). Patients reported their pain levels daily using the Wong-Baker FACES Pain Rating Scale. The following cutoffs were determined as high levels of anxiety: STAI (adult) > 44, STAI (child) > 36, and mYPAS-SF ≥ 30. FINDINGS: No significant differences were found in the STAI, mYPAS-SF, and Wong-Baker FACES Pain Rating Scale scores of the patients between the intervention and control group. Overall statistics showed that parents had significantly higher postoperative state anxiety levels toward female children (44.93 ± 9.01) compared to male children (40.18 ± 9.89). Preoperative and postoperative parental state anxiety levels were correlated with the child's postoperative anxiety. Furthermore, children's postoperative state anxiety was slightly correlated with postoperative pain. CONCLUSIONS: Short-term use of our deep breathing exercises was ineffective in reducing incidences of perioperative pain and anxiety in pediatric orthopedic patients. A longer period of deep breathing administration may be required for the intervention to be effective. Parental anxiety may have an effect on anxiety levels in children, and postoperative parental anxiety may be affected by the gender of the child.

Lysine methylation modifications in tumor immunomodulation and immunotherapy: regulatory mechanisms and perspectives.

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.

Reciprocal interactions between lncRNAs and MYC in colorectal cancer: partners in crime.

Proto-oncogenic MYC is frequently dysregulated in colorectal cancer (CRC). In the past decades, long noncoding RNAs (lncRNAs) have emerged as important regulators in cancers, acting as scaffolds, molecular decoys, post-transcriptional regulators, and others. Interestingly, lncRNAs are able to control MYC expression both at transcriptional and post-transcriptional levels. It is suggested that the reciprocal interaction of MYC and lncRNAs often occurs in CRC. MYC can affect the cell fate by promoting or inhibiting the transcription of some lncRNAs. At the same time, some lncRNAs can also affect MYC expression or transcriptional activity, and in turn decide the cell fate. In this review we summarized the current knowledge about the MYC and lncRNA axis, focusing on its mutual regulation, roles in CRC, and proposed potential therapeutic prospects for CRC treatment.

Single-gold etching at the hypercarbon atom of C-centred hexagold(I) clusters protected by chiral N-heterocyclic carbenes.

Chemical etching of nano-sized metal clusters at the atomic level has a high potential for creating metal number-specific structures and functions that are difficult to achieve with bottom-up synthesis methods. In particular, precisely etching metal atoms one by one from nonmetallic element-centred metal clusters and elucidating the relationship between their well-defined structures, and chemical and physical properties will facilitate future materials design for metal clusters. Here we report the single-gold etching at a hypercarbon centre in gold(I) clusters. Specifically, C-centred hexagold(I) clusters protected by chiral N-heterocyclic carbenes are etched with bisphosphine to yield C-centred pentagold(I) (CAuI5) clusters. The CAuI5 clusters exhibit an unusually large bathochromic shift in luminescence, which is reproduced theoretically. The etching mechanism is experimentally and theoretically suggested to be a tandem dissociation-association-elimination pathway. Furthermore, the vacant site of the central carbon of the CAuI5 cluster can accommodate AuCl, allowing for post-functionalisation of the C-centred gold(I) clusters.

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Soil matrix infiltration is an important pathway for plantations to obtain water, which affects ecological benefits and water conservation function of plantations. The changes of soil matrix infiltration and its influencing factors in different growth stages of Chinese fir plantations remain unclear. We measured soil matrix infiltration process using a tension infiltrometer in Chinese fir plantations (5, 8, 11, and 15 years old) of Beijiang River Forest Farm in Rongshui, Guangxi, and analyzed soil basic physicochemical properties to identify the dominant factors influencing soil matrix infiltration. The results showed that initial infiltration rate, stable infiltration rate, and cumulative infiltration increased with stand ages. The ranges of different stand ages were 141-180 mm·h-1, 109-150 mm·h-1, and 188-251 mm, respectively. The initial infiltration rate, stable infiltration rate, and cumulative infiltration were significantly positively correlated with soil capillary porosity, soil organic matter, soil water stable macroaggregate, sand content, and clay content, while negatively correlated with soil bulk density and silt content. Early thinning had a positive effect on soil matrix infiltration, but thinning measures after 11 years did not enhance soil matrix infiltration further. Philip model was optimal for describing soil matrix infiltration process in this region. In conclusion, soil matrix infiltration capacity of Chinese fir plantations gradually increased from young to middle-aged stands, but matrix infiltration capacity tended to stabilize after 11 years old. Silt content and water stable macroaggregate were the dominant factors influencing matrix infiltration.

Direct extraction of lithium from ores by electrochemical leaching.

With the rapid increase in lithium consumption for electric vehicle applications, its price soared during the past decade. To secure a reliable and cost-effective supply chain, it is critical to unlock alternative lithium extraction resources beyond conventional brine. In this study, we develop an electrochemical method to directly leach lithium from α-phase spodumene. We find the H2O2 promoter can significantly reduce the leaching potential by facilitating the electron transfer and changing the reaction path. Upon leaching, ß-phase spodumene shows a typical phase transformation to HAlSi2O6, while leached α-phase remains its original crystal phase with a lattice shrinkage. To demonstrate the scale-up potential of electrochemical leaching, we design a catalyst-modified high-throughput current collector for high loading of suspended spodumene, achieving a leaching current of 18 mA and a leaching efficiency of 92.2%. Electrochemical leaching will revolutionize traditional leaching and recycling processes by minimizing the environmental footprint and energy consumption.

'Passivated Precursor' Approach to All-Alkynyl-Protected Gold Nanoclusters and Total Structure Determination of Au130.

A 'passivated precursor' approach is developed for the efficient synthesis and isolation of all-alkynyl-protected gold nanoclusters. Direct reduction of dpa-passivated precursor Au-dpa (Hdpa=2,2'-dipyridylamine) in one-pot under ambient conditions gives a series of clusters including Au22(C≡CR)18 (R=-C6H4-2-F), Au36(C≡CR)24, Au44(C≡CR)28, Au130(C≡CR)50, and Au144(C≡CR)60. These clusters can be well separated via column chromatography. The overall isolation yield of this series of clusters is 40 % (based on gold), which is much improved in comparison with previous approaches. It is notable that the molecular structure of the giant cluster Au130(C≡CR)50 is revealed, which presents important information for understanding the structure of the mysterious Au130 nanoclusters. Theoretical calculations indicated Au130(C≡CR)50 has a smaller HOMO-LUMO gap than Au130(S-C6H4-4-CH3)50. This facile and reliable synthetic approach will greatly accelerate further studies on all-alkynyl-protected gold nanoclusters.

Deciphering the role of extracellular polymeric substances in the adsorption and biotransformation of organic micropollutants during anaerobic wastewater treatment.

Extracellular polymeric substances (EPS) participate in the removal of organic micropollutants (OMPs), but the primary pathways of removal and detailed mechanisms remain elusive. We evaluated the effect of EPS on removal for 16 distinct chemical classes of OMPs during anaerobic digestion (AD). The results showed that hydrophobic OMPs (HBOMPs) could not be removed by EPS, while hydrophilic OMPs (HLOMPs) were amenable to removal via adsorption and biotransformation of EPS. The adsorption and biotransformation of HLOMPs by EPS accounted up to 19.4 ± 0.9 % and 6.0 ± 0.8 % of total removal, respectively. Further investigations into the adsorption and biotransformation mechanisms of HLOMPs by EPS were conducted utilizing spectral, molecular dynamics simulation, and electrochemical analysis. The results suggested that EPS provided abundant binding sites for the adsorption of HLOMPs. The binding of HLOMPs to tryptophan-like proteins in EPS formed nonfluorescent complexes. Hydrogen bonds, hydrophobic interactions and water bridges were key to the binding processes and helped stabilize the complexes. The biotransformation of HLOMPs by EPS may be attributed to the presence of extracellular redox active components (c-type cytochromes (c-Cyts), c-Cyts-bound flavins). This study enhanced the comprehension for the role of EPS on the OMPs removal in anaerobic wastewater treatment.

Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2.

Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation-specific homologous factor (EHF), a member of the E26 transformation-specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma-associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor-associated macrophages (TAMs) through the C-C motif chemokine 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co-expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development.

CeO2 nanocages with tetra-enzyme mimetic activities for dual-channel ratiometric colorimetric detection of microcystins-LR.

BACKGROUND: Microcystin-leucine-arginine (MC-LR) produced by various cyanobacteria during harmful algal bloom poses serious threats to drinking water safety and human health. Conventional chromatography-based detection methods require expensive instruments and complicated sample pretreatment, limiting their application for on-site detection. Colorimetric aptasensors are simple and rapid, and are amenable to fast detection. However, they provide only one output signal, resulting in poor sensitivity and accuracy. Dual-channel ratiometric colorimetric method based on the peroxidase-like activity of nanozyme can achieve self-calibration by recording two reverse signals, providing significantly enhanced sensitivity and accuracy. RESULTS: CeO2 nanocages (CeO2 NCs) with tetra-enzyme mimetic activities (oxidase-, peroxidase-, catalase- and superoxide dismutase-like activities) were facilely synthesized using zeolitic imidazolate framework-67 (ZIF-67) as sacrificial template. The peroxidase-like activity of CeO2 NCs can be regulated by DNA, and it showed opposite response to two chromogenic substrates (2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and 3,3',5,5'-tetramethylbenzidine (TMB)), which was mainly attributed to the changed affinity. On the basis of MC-LR aptamer-tunable peroxidase-like activity of CeO2 NCs in TMB and ABTS channel, a dual-channel ratiometric colorimetric aptasensor was constructed for detection of MC-LR. Compared with conventional single-signal colorimetric assays, the proposed method showed lower limit of detection (0.66 pg mL-1) and significantly enhanced sensitivity. Moreover, the practicability of the ratiometric colorimetric assay was demonstrated by detecting MC-LR in real water samples, and satisfactory recoveries (94.9-101.9 %) and low relative standard deviations (1.6-6.3 %) were obtained. SIGNIFICANCE: This work presents a nanozyme-based ratiometric colorimetric aptasensor for MC-LR detection by recording the reverse responses of two chromogenic reactions. Benefiting from the self-calibration function, the method can achieve higher sensitivity and accuracy. The short detection time and practical application in real water samples show great potential for environmental monitoring.