Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2α.

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.

A multifunctional fluorescent probe for sequential detection of hydrogen sulfide and pH in foodstuffs, living cells and mice.

BACKGROUND: Cancer as a leading cause of premature death worldwide has become a major threat to human health due to the high incidence and mortality. Monitoring tumor markers are reliable and significantly important for early detection of cancers. In complex biological systems, it is of great urgency but still remains challenging to conceive a fluorescent probe with multiple tumor markers detection property. Hydrogen sulfide (H2S) and pH are two target biomarkers for diagnosis of early cancer. The preparation of a novel probe with H2S and pH dual detection functions is highly anticipated. RESULTS: Herein, a novel sequential detection probe HTPQ-HS for H2S and pH has been developed. In this system, HPQ (2-(2 -hydroxyphenyl)-4(3H)-quinazolinone) structure combined with triphenylamine is applied as the fluorophore, and 2, 4-dinitrophenylsulfonyl group is used as the recognition group. In the presence of H2S, HTPQ-HS is transformed into product HTPQ-OH which shows fluorescence enhancement (29-fold) at 525 nm in less than 4 min and further displays repeatable acid-base responsive ability. HTPQ-HS is able to sequentially response to H2S and pH in living cells and does not react directly with pH. Owing to the low cytotoxicity, HTPQ-HS is able to detect exogenous and endogenous H2S in colon cancer cells and mice, monitor H2S in inflammation model and in foodstuffs. As the environment changes from acidic to alkaline, the fluorescence intensity ratio (I470/I530) of product HTPQ-OH changes remarkably, illustrating the ratiometric fluorescent responsiveness to pH. SIGNIFICANCE AND NOVELTY: A multifunctional fluorescent probe HTPQ-HS for sequential detection of H2S and pH is synthesized. Probe HTPQ-OH realizes the monitoring of dynamic changes in intracellular pH and displays prospective application in security printing. We expect that our work could offer an important guidance on the development of multifunctional fluorescent probes for visualizing H2S and pH in biology and environment.

Lithium Borohydride Nanorods: Self-Assembling Growth and Remarkable Hydrogen Cycling Properties.

Nanostructured metal hydrides with unique morphology and improved hydrogen storage properties have attracted intense interests. However, the study of the growth process of highly active borohydrides remains challenging. Herein, for the first time the synthesis of LiBH4 nanorods through a hydrogen-assisted one-pot solvothermal reaction is reported. Reaction of n-butyl lithium with triethylamine borane in n-hexane under 50 bar of H2 at 40-100 °C gives rise to the formation of the [100]-oriented LiBH4 nanorods with 500-800 nm in diameter, whose growth is driven by orientated attachment and ligand adsorption. The unique morphology enables the LiBH4 nanorods to release hydrogen from ≈184 °C, 94 °C lower than the commercial sample (≈278 °C). Hydrogen release amounts to 13 wt% within 40 min at 450 °C with a stable cyclability, remarkably superior to the commercial LiBH4 (≈9.1 wt%). More importantly, up to 180 °C reduction in the onset temperature of hydrogenation is successfully attained by the nanorod sample with respect to the commercial counterpart. The LiBH4 nanorods show no foaming during dehydrogenation, which improves the hydrogen cycling performance. The new approach will shed light on the preparation of nanostructured metal borohydrides as advanced functional materials.

The Effect of Pixel Design and Operation Conditions on Linear Output Range of 4T CMOS Image Sensors.

We analyze several factors that affect the linear output range of CMOS image sensors, including charge transfer time, reset transistor supply voltage, the capacitance of integration capacitor, the n-well doping of the pinned photodiode (PPD) and the output buffer. The test chips are fabricated with 0.18 µm CMOS image sensor (CIS) process and comprise six channels. Channels B1 and B2 are 10 µm pixels and channels B3-B6 are 20 µm pixels, with corresponding pixel arrays of 1 × 2560 and 1 × 1280 respectively. The floating diffusion (FD) capacitance varies from 10 fF to 23.3 fF, and two different designs were employed for the n-well doping in PPD. The experimental results indicate that optimizing the FD capacitance and PPD design can enhance the linear output range by 37% and 32%, respectively. For larger pixel sizes, extending the transfer gate (TG) sampling time leads to an increase of over 60% in the linear output range. Furthermore, optimizing the design of the output buffer can alleviate restrictions on the linear output range. The lower reset voltage for noise reduction does not exhibit a significant impact on the linear output range. Furthermore, these methods can enhance the linear output range without significantly amplifying the readout noise. These findings indicate that the linear output range of pixels is not only influenced by pixel design but also by operational conditions. Finally, we conducted a detailed analysis of the impact of PPD n-well doping concentration and TG sampling time on the linear output range. This provides designers with a clear understanding of how nonlinearity is introduced into pixels, offering valuable insight in the design of highly linear pixels.

Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development.

Family with sequence similarity 20 member C (FAM20C) is a Golgi casein kinase that phosphorylates extracellularly-secreted regulatory proteins involved in bone development and mineralization, but its specific role in bone development is still largely unknown. In this study, to examine the specific mechanisms that FAM20C influences bone development, we cross-bred Osx-Cre with FAM20Cflox/flox mice to establish a Osx-Cre; FAM20Cflox/flox knockout (oKO) mouse model; FAM20C was KO in pre-osteoblasts. oKO development was examined at 1-10 weeks, in which compared to control FAM20Cflox/flox, they had lower body weights and bone tissue mineralization. Furthermore, oKO had lower bone volume fractions, thickness, and trabecular numbers, along with higher degrees of trabecular separation. These mice also had decreased femoral metaphyseal cartilage proliferation layer, along with thickened hypertrophic layer and increased apoptotic cell counts. Transcriptomic analysis found that differentially-expressed genes in oKO were concentrated in the osteoclast differentiation pathway, in line with increased osteoclast presence. Additionally, up-regulation of osteoclast-related, and down-regulation of osteogenesis-related genes, were identified, in which the most up-regulated genes were signal regulatory protein ß-1 family (Sirpb1a-c) and mitogen-activated protein kinase 13. Overall, FAM20C KO in pre-osteoblasts leads to abnormal long bone development, likely due to subsequent up-regulation of osteoclast differentiation-associated genes.

Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies.

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients. Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%). Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC.

Relationship between hepatic surgical margins of colorectal cancer liver metastases and prognosis: A review.

Colorectal cancer (CRC) remains a significant global health concern, as characterized by its high mortality rate ranking second among all the leading causes of death. The liver serves as the primary site of CRC metastasis, and the occurrence of liver metastasis is a significant contributor to mortality among patients diagnosed with CRC. The survival rate of patients with colorectal liver metastasis has significantly increased with the advancement of comprehensive tumor therapy. However, radical surgery remains the key factor. Since there are frequently multiple liver metastases, which are prone to recurrence after surgery, it is crucial to preserve as much liver parenchyma as possible without affecting the prognosis. The issue of surgical margins plays a crucial role in this regard. In this review, we begin by examining the occurrence of positive surgical margins in liver metastases of patients diagnosed with CRC. We aim to define positive margins in hepatic surgery, examine the relationship between margins and prognosis and establish a foundation for future research in this field.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Genomic and epigenetic characterization of the arsenic-induced oncogenic microRNA-21.

As one of the first identified oncogenic microRNAs, the precise details concerning the transcriptional regulation and function of microRNA-21 (miR-21) are still not completely established. The miR-21 gene is situated on chromosome 17q23.2, positioned at the 3'-UTR of the gene that encodes vacuole membrane protein-1 (VMP1). In this current study, we presented evidence indicating that miR-21 possesses its own gene promoter, which can be found in the intron 10 of the VMP1 gene. Chromatin immunoprecipitation followed by global DNA sequencing (ChIP-seq) revealed the presence of a broad H3K4me3 peak spanning the entire gene body of the primary miR-21 and the existence of super-enhancer clusters in the close proximity to both the miR-21 gene promoter and the transcription termination site in arsenic (As3+)-induced cancer stem-like cells (CSCs) and human induced pluripotent stem cells (hiPSCs). In non-transformed human bronchial epithelial cells (BEAS-2B), As3+ treatment enhanced Nrf2 binding to both the host gene VMP1 of miR-21 and the miR-21 gene. Knockout of Nrf2 inhibited both the basal and As3+-induced expressions of miR-21. Furthermore, the As3+-enhanced Nrf2 peaks in ChIP-seq fully overlap with these super-enhancers enriched with H3K4me1 and H3K27ac in the miR-21 gene, suggesting that Nrf2 may coordinate with other transcription factors through the super-enhancers to regulate the expression of miR-21 in cellular response to As3+. These findings demonstrate the unique genetic and epigenetic characteristics of miR-21 and may provide insights into understanding the novel mechanisms linking environmental As3+ exposure and human cancers.

A lysosome-targeted fluorescent probe based on a BODIPY structure for Cys/Hcy detection.

Cysteine (Cys) and homocysteine (Hcy) are important biothiols in living organisms. They play important roles in a variety of physiological and pathological processes. Therefore, it is very important to design an optical probe for the selective detection of Cys/Hcy. Herein, we report the design and synthesis of a fluorescent probe NBD-B-T based on a boron-dipyrromethene (BODIPY) structure, which showed an excellent lysosome targeting ability and an outstanding Cys/Hcy detection capacity. For NBD-B-T, the sensing group 7-nitro-2,1,3-benzoxadiazole (NBD) and the lysosomal targeting group morpholine were introduced. The results show that the NBD-B-T probe can detect Cys/Hcy with fluorescence emission turn-on performance. The low detection limits of this probe are about 76.0 nM for Hcy and 97.6 nM for Cys, respectively. The NBD-B-T probe has a low detection limit, high stability, and excellent selectivity and sensitivity. More importantly, the NBD-B-T can target lysosome, and simultaneously detect the Cys/Hcy in living cells.

Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection.

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 µmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 µg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 (5) and AZD5099 (6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 (6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 µg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy.

An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In this study, we obtained spectra of IMM--H014 and related substances in deuterated chloroform using dimethyl terephthalate (DMT) as the internal standard reference. Quantification was performed using the 1H resonance signals at δ 8.13 ppm for DMT and δ 6.5-7.5 ppm for IMM-H014 and its related substances. Several key experimental parameters were investigated and optimized, such as pulse angle and relaxation delay. Methodology validation was conducted based on the International Council for Harmonization guidelines and verified with satisfactory specificity, precision, linearity, accuracy, robustness, and stability. In addition, the calibration results of the samples were consistent with those obtained from the mass balance method. Thus, this research provides a reliable and practical protocol for purity analysis of IMM-H014 and its critical impurities and contributes to subsequent clinical quality control research.

Rhesus monkeys exhibiting spontaneous ritualistic behaviors resembling obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric disorder that affects ∼2%-3% of the population globally. Studying spontaneous OCD-like behaviors in non-human primates may improve our understanding of the disorder. In large rhesus monkey colonies, we found 10 monkeys spontaneously exhibiting persistent sequential motor behaviors (SMBs) in individual-specific sequences that were repetitive, time-consuming and stable over prolonged periods. Genetic analysis revealed severely damaging mutations in genes associated with OCD risk in humans. Brain imaging showed that monkeys with SMBs had larger gray matter (GM) volumes in the left caudate nucleus and lower fractional anisotropy of the corpus callosum. The GM volume of the left caudate nucleus correlated positively with the daily duration of SMBs. Notably, exposure to a stressor (human presence) significantly increased SMBs. In addition, fluoxetine, a serotonergic medication commonly used for OCD, decreased SMBs in these monkeys. These findings provide a novel foundation for developing better understanding and treatment of OCD.

Holographic imaging platform for particle discrimination based on simultaneous mass density and refractive index measurements.

Real-time detection, classification and identification of aerosol particles is crucial in various industries and public health areas. In order to circumvent the limitations of existing particle analysis methods for efficient discrimination, we demonstrate a compact digital in-line holographic microscopy platform with an inertial spectrometer for simultaneous measurement of two independent fingerprint parameters at single species level. In particular, by interrogating the particle location and size captured with the platform, particle mass density can be estimated. Furthermore, by employing Monte Carlo fitting to the Lorenz-Mie theory, the refractive index of each particle can also be extracted from the interference patterns. It is demonstrated that the combination of mass density and optical density characterization unambiguously enhances the discriminatory power of the system, especially when dealing with particles that exhibit similar mass densities but distinctive refractive indices or vice versa. This innovative approach represents a significant advancement in particle characterization and composition identification, with potential applications in various industrial, scientific, and research domains. An iOS-based app interface is then customized for wireless controlling of the CMOS imager, image acquisition, reconstruction, and data analysis. The imaging platform proposed in this work has prominent advantages including compactness, accuracy, efficiency, high throughput, and remote sensing capability, which is especially relevant for applications where on-site/remote metrology and identification of particles is required.

Tumor suppressive activity of AHR in environmental arsenic-induced carcinogenesis.

The aryl hydrocarbon receptor (AHR) is a highly conserved pleiotropic transcription factor that senses environmental pollutants, microbial products, and endogenous ligands. The transcriptional targets of AHR include phase I and phase II detoxification enzymes, as well as numerous signaling molecules that affect a wide spectrum of biological and biochemical processes in a manner of cellular context-dependent. In this review, we systematically assess the latest discoveries of AHR in carcinogenesis with an emphasis on its tumor suppressor-like property that represses the expression of genes in oncogenic signaling pathways. Additionally, we outline recent progress in our studies on the interaction among AHR, TGFb and NRF2 in cellular responses to arsenic and malignant transformation. Our findings indicate that AHR antagonized TGFb and NRF2, suggesting that AHR could serve as a potential tumor suppressor in arsenic-induced carcinogenesis. Notably, while AHR can exhibit both oncogenic and tumor-suppressive properties in cancer development and the generation of the cancer stem-like cells (CSCs), the tumor suppressor-like effect of AHR warrants further extensive exploration for the prevention and clinical treatment of cancers.

Comparison of internet-based and face-to-face cognitive behavioral therapy for obsessive-compulsive disorder: A systematic review and network meta-analysis.

Cognitive behavioral therapy (CBT) is widely recognized as an effective treatment for obsessive-compulsive disorder (OCD). However, few patients are able to receive CBT. Internet-based CBT (ICBT) may be able to overcome this problem. In this study, we aimed to compare the efficacy of CBT, therapist-guided ICBT (TG-ICBT), unguided ICBT (UG-ICBT), and none therapist-guided ICBT (NTG-ICBT) by a network meta-analysis. The primary outcome was the mean change in OCD severity measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). The secondary outcomes included the severity of depressive symptoms, side effects, and cost-effectiveness. A total of 25 trials with 1642 participants were included. We found that the efficacy of CBT was superior to that of TG-ICBT. The mean improvement in Y-BOCS/CY-BOCS scores was higher in CBT group than in UG-ICBT group, but this difference was not statistically significant. The efficacy did not differ significantly between TG-ICBT and UG-ICBT. CBT, TG-ICBT, and UG-ICBT were all more effective than the psychological placebo, waiting list, and pill placebo. In terms of efficacy, CBT combined with drug therapy was better than CBT, TG-ICBT, and UG-ICBT. Sensitivity analyses supported these findings. Based on the current evidence, we recommend TG-ICBT when CBT is not available. However, it is undeniable that UG-ICBT also has the potential to be an effective alternative to CBT. More evidence is needed to support this possibility.

Discovery of isatin-ß-methyldithiocarbazate derivatives as New Delhi metallo- ß-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates.

New Delhi metallo-ß-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all ß-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

[Research progress on attention level evaluation based on electroencephalogram signals].

Attention level evaluation refers to the evaluation of people's attention level through observation or experimental testing, and its research results have great application value in education and teaching, intelligent driving, medical health and other fields. With its objective reliability and security, electroencephalogram signals have become one of the most important technical means to analyze and express attention level. At present, there is little review literature that comprehensively summarize the application of electroencephalogram signals in the field of attention evaluation. To this end, this paper first summarizes the research progress on attention evaluation; then the important methods for electroencephalogram attention evaluation are analyzed, including data preprocessing, feature extraction and selection, attention evaluation methods, etc.; finally, the shortcomings of the current development in the field of electroencephalogram attention evaluation are discussed, and the future development trend is prospected, to provide research references for researchers in related fields.

Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors.

Dihydrofolate reductase (DHFR), a core enzyme of folate metabolism, plays a crucial role in the biosynthesis of purines and thymidylate for cell proliferation and growth in both prokaryotic and eukaryotic cells. However, the development of new DHFR inhibitors is challenging due to the limited number of scaffolds available for drug development. Hence, we designed and synthesized a new class of DHFR inhibitors with a 1,3-diamino-7H-pyrrol[3,2-f]quinazoline derivative (PQD) structure bearing condensed rings. Compound 6r exhibited therapeutic effects on mouse models of systemic infection and thigh infection caused by methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. Moreover, methyl-modified PQD compound 8a showed a strong efficacy in a murine model of breast cancer, which was better than the effects of taxol. The findings showcased in this study highlight the promising capabilities of novel DHFR inhibitors in addressing bacterial infections as well as breast cancer.

Degradation of Levofloxacin by a green zero-valent iron-loaded carbon composite activating peroxydisulfate system: Reactivity, products and mechanism.

In this study, a green zero-valent iron-loaded carbon composite (ZVI-SCG) was synthesized using coffee grounds and FeCl3 solution through two-steps method, and the synthesized ZVI-SCG was used in the activation of peroxydisulfate (PDS) to degrade Levofloxacin (LEX). Results revealed that ZVI-SCG exhibited a great potential for LEX removal by adsorption and catalytic degradation in the ZVI-SCG/PDS system, and 99% of LEX was removed in the ZVI-SCG/PDS system within 60 min. ZVI-SCG/PDS system showed a high reactivity toward LEX degradation under realistic environmental conditions. Also, the ZVI-SCG/PDS system could effectively degrade several quinolone antibiotics including gatifloxacin, ciprofloxacin and LEX in single and simultaneous removal modes. A potential reaction mechanism of LEX degradation by ZVI-SCG/PDS system was proposed, SO4•-, HO•, O2•- and 1O2 involved in radical and non-radical pathways took part in catalytic degradation of LEX by ZVI-SCG/PDS system, but HO• might be the main reactive species for LEX degradation. The possible degradation pathway of LEX was also proposed based on the identified ten intermediate products, LEX degradation was successfully achieved through decarboxylation, opening ring and hydroxylation processes. The potential toxicity of LEX and its oxidation products decreased significantly after treatment. This study provides a promising strategy of water treatment for the antibiotics-containing wastewater.