Dopamine promotes osteogenic differentiation of PDLSCs by activating DRD1 and DRD2 during orthodontic tooth movement via ERK1/2 signaling pathway.

Introduction: Orthodontic tooth movement (OTM) involves complex interactions between mechanical forces and periodontal tissue adaptation, mainly mediated by periodontal ligament cells, including periodontal ligament stem cells (PDLSCs), osteoblasts, and osteoclasts. Dopamine (DA), a neurotransmitter known for its critical role in bone metabolism, is investigated in this study for its potential to enhance osteogenic differentiation in PDLSCs, which are pivotal in OTM. This study examined the potential of DA to facilitate OTM by binding to DA receptors (D1R and D2R) and activating the ERK1/2 signaling pathway. We propose that DA's interaction with these receptors on PDLSCs could enhance osteogenic differentiation, thereby accelerating bone remodeling and reducing the duration of orthodontic treatments, which offering a novel approach to improve clinical outcomes in orthodontic care. Methods: This study utilized a rat OTM model, micro-CT, histological analyses, and in vitro assays to investigate dopamine's effect on osteogenesis. PDLSCs were cultured and treated with DA, and cytotoxicity, osteogenic differentiation, gene and protein expression assessed. Results: Dopamine administration significantly increased trabecular bone density and osteogenic marker expression in an OTM rat model. In vitro, DA at 10 nM optimally promoted human PDLSCs osteogenesis without affecting proliferation. Blocking DA receptors or inhibiting the ERK1/2 pathway attenuated these effects, underscoring the importance of dopaminergic signaling in tension-induced osteogenesis during OTM. Conclusion: Taken together, our study reveals that local dopamine administration at a concentration of 10 nM not only enhances tension-induced osteogenesis in vivo but also significantly promotes osteogenic differentiation of PDLSCs in vitro through D1 and D2 receptor-mediated ERK1/2 signaling pathway activation.

Assessing the predictability of surrogate safety measures as crash precursors based on vehicle trajectory data prior to crashes.

This study aims to investigate the predictability of surrogate safety measures (SSMs) for real-time crash risk prediction. We conducted a year-long drone video collection on a busy freeway in Nanjing, China, and collected 20 rear-end crashes. The predictability of SSMs was defined as the probability of crash occurrence when using SSMs as precursors to crashes. Ridge regression models were established to explore contributing factors to the predictability of SSMs. Four commonly used SSMs were tested in this study. It was found that modified time-to-collision (MTTC) outperformed other SSMs when the early warning capability was set at a minimum of 1 s. We further investigated the cost and benefit of SSMs in safety interventions by evaluating the number of necessary predictions for successful crash prediction and the proportion of crashes that can be predicted accurately. The result demonstrated these SSMs were most efficient in proactive safety management systems with an early warning capability of 1 s. In this case, 308, 131, 281, and 327,661 predictions needed to be made before a crash could be successfully predicted by TTC, MTTC, DRAC, and PICUD, respectively, achieving 75 %, 85 %, 35 %, and 100 % successful crash identifications. The ridge regression results indicated that the predefined threshold had the greatest impact on the predictability of all tested SSMs.

A new 3,4-dihydroisocoumarin and an antiinflammatory coumarin from the roots of Saposhnikovia divaricata (Turcz.) Schischk.

Phytochemical investigation of the roots of Saposhnikovia divaricata (Turcz.) Schischk resulted in the isolation of twelve coumarin derivatives including one new 3,4-dihydroisocoumarin (1) and eleven known 3,4-unsubstituted coumarins (2-12). Structural elucidation of compounds 1-12 was established by 1D and 2D NMR spectra referring to the literature, together with high-resolution mass spectrometric analysis. LPS-induced RAW264.7 inflammatory cell model was used to determine the potential antiinflammation activity of all the isolated compounds in vitro. The results showed that compound 3 significantly inhibited the production of lipopolysaccharide (LPS)-induced NO in macrophages (IC50 = 4.54 ± 1.71 µM), more active than the positive control (L-NMMA).

The causal association between artificial sweeteners and the risk of cancer: a Mendelian randomization study.

Artificial sweeteners (ASs) have been widely added to food and beverages because of their properties of low calories and sweet taste. However, whether the consumption of ASs is causally associated with cancer risk is not clear. Here, we utilized the two-sample Mendelian randomization (MR) method to study the potential causal association. Genetic variants like single-nucleotide polymorphisms (SNPs) associated with exposure (AS consumption) were extracted from a genome-wide association study (GWAS) database including 64 949 Europeans and the influence of confounding was removed. The outcome was from 98 GWAS data and included several types of cancers like lung cancer, colorectal cancer, stomach cancer, breast cancer, and so on. The exposure-outcome SNPs were harmonized and then MR analysis was performed. The inverse-variance weighted (IVW) with random effects was used as the main analytical method accompanied by four complementary methods: MR Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses consisted of heterogeneity, pleiotropy, and leave-one-out analysis. Our results demonstrated that ASs added to coffee had a positive association with high-grade and low-grade serous ovarian cancer; ASs added to tea had a positive association with oral cavity and pharyngeal cancers, but a negative association with malignant neoplasm of the bronchus and lungs. No other cancers had a genetic causal association with AS consumption. Our MR study revealed that AS consumption had no genetic causal association with major cancers. Larger MR studies or RCTs are needed to investigate small effects and support this conclusion.

The Associations of Prenatal Exposure to Fine Particulate Matter and Its Chemical Components with Allergic Rhinitis in Children and the Modification Effect of Polyunsaturated Fatty Acids: A Birth Cohort Study.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) have been shown to protect against fine particulate matter <2.5µm in aerodynamic diameter (PM2.5)-induced hazards. However, limited evidence is available for respiratory health, particularly in pregnant women and their offspring. OBJECTIVES: We aimed to investigate the association of prenatal exposure to PM2.5 and its chemical components with allergic rhinitis (AR) in children and explore effect modification by maternal erythrocyte PUFAs. METHODS: This prospective birth cohort study involved 657 mother-child pairs from Guangzhou, China. Prenatal exposure to residential PM2.5 mass and its components [black carbon (BC), organic matter (OM), sulfate (SO42-), nitrate (NO3-), and ammonium (NH4+)] were estimated by an established spatiotemporal model. Maternal erythrocyte PUFAs during pregnancy were measured using gas chromatography. The diagnosis of AR and report of AR symptoms in children were assessed up to 2 years of age. We used Cox regression with the quantile-based g-computation approach to assess the individual and joint effects of PM2.5 components and examine the modification effects of maternal PUFA levels. RESULTS: Approximately 5.33% and 8.07% of children had AR and related symptoms, respectively. The average concentration of prenatal PM2.5 was 35.50±5.31 µg/m3. PM2.5 was positively associated with the risk of developing AR [hazard ratio (HR)=1.85; 95% confidence interval (CI): 1.16, 2.96 per 5 µg/m3] and its symptoms (HR=1.79; 95% CI: 1.22, 2.62 per 5 µg/m3) after adjustment for confounders. Similar associations were observed between individual PM2.5 components and AR outcomes. Each quintile change in a mixture of components was associated with an adjusted HR of 3.73 (95% CI: 1.80, 7.73) and 2.69 (95% CI: 1.55, 4.67) for AR and AR symptoms, with BC accounting for the largest contribution. Higher levels of n-3 docosapentaenoic acid and lower levels of n-6 linoleic acid showed alleviating effects on AR symptoms risk associated with exposure to PM2.5 and its components. CONCLUSION: Prenatal exposure to PM2.5 and its chemical components, particularly BC, was associated with AR/symptoms in early childhood. We highlight that PUFA biomarkers could modify the adverse effects of PM2.5 on respiratory allergy. https://doi.org/10.1289/EHP13524.

Ultrasensitive colorimetric detection of creatinine via its dual binding affinity for silver nanoparticles and silver ions.

Creatinine is an important biomarker for the diagnosis of chronic kidney disease (CKD). Recently, it has been reported that the concentration of salivary creatinine correlates well with the concentration of serum creatinine, which makes the former useful for the development of non-invasive and point-of-care (POC) detection for CKD diagnosis. However, there exists a technical challenge in the rapid detection of salivary creatinine at low concentrations of 3-18 µM when using the current kidney function test strips as well as the traditional methods employed in hospitals. Herein, we demonstrate a simple, sensitive colorimetric assay for the detection of creatinine with a limit-of-detection (LOD) down to the nanomolar level. Our approach utilises the dual binding affinity of creatinine for citrate-capped silver nanoparticles (Ag NPs) and Ag(i) ions, which can trigger the aggregation of Ag NPs and thus lead to the colour change of a sample. The quantitative detection of creatinine was achieved using UV-Vis spectroscopy with a LOD of 6.9 nM in artificial saliva and a linear dynamic range of 0.01-0.06 µM. This method holds promise to be further developed into a POC platform for the CKD diagnosis.

Lipid levels and risk of acute pancreatitis using bidirectional Mendelian randomization.

Previous studies found lipid levels, especially triglycerides (TG), are associated with acute pancreatitis, but their causalities and bi-directions were not fully examined. We determined whether abnormal levels of TG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) are precursors and/or consequences of acute pancreatitis using bidirectional two-sample Mendelian randomization (MR) with two non-overlapping genome-wide association study (GWAS) summary statistics for lipid levels and acute pancreatitis. We found phenotypic associations that both higher TG levels and lower HDL-C levels contributed to increased risk of acute pancreatitis. Our GWAS meta-analysis of acute pancreatitis identified seven independent signals. Genetically predicted TG was positively associated with acute pancreatitis when using the variants specifically associated with TG using univariable MR [Odds ratio (OR), 95% CI 2.02, 1.22-3.31], but the reversed direction from acute pancreatitis to TG was not observed (mean difference = 0.003, SE = 0.002, P-value = 0.138). However, a bidirectional relationship of HDL-C and acute pancreatitis was observed: A 1-SD increment of genetically predicted HDL-C was associated with lower risk of acute pancreatitis (OR, 95% CI 0.84, 0.76-0.92) and genetically predisposed individuals with acute pancreatitis have, on average, 0.005 SD lower HDL-C (mean difference = - 0.005, SE = 0.002, P-value = 0.004). Our MR analysis confirms the evidence of TG as a risk factor of acute pancreatitis but not a consequence. A potential bidirectional relationship of HDL-C and acute pancreatitis occurs and raises the prospect of HDL-C modulation in the acute pancreatitis prevention and treatment.

Glycine betaine modulates extracellular polymeric substances to enhance microbial salinity tolerance.

High salinity inhibits microbial activity in the bioremediation of saline wastewater. To alleviate osmotic stress, glycine betaine (GB), an osmoprotectant, is added to enhance the secretion of extracellular polymeric substances (EPS). These EPS are pivotal in withstanding environmental stressors, yet the intricate interplay between GB supplementation and microbial responses through EPS modifications-encompassing composition, molecular architecture, and electrochemical features-remains elusive in hypersaline conditions. Here we show microbial strategies for salinity endurance by investigating the impact of GB on the dynamic alterations of EPS properties. Our findings reveal that GB supplementation at 3.5% salinity elevates the total EPS (T-EPS) content from 12.50 ± 0.05 to 24.58 ± 0.96 mg per g dry cell weight. The observed shift in zeta potential from -28.95 to -6.25 mV at 0% and 3.5% salinity, respectively, with GB treatment, indicates a reduction in electrostatic repulsion and compaction. Notably, the EPS protein secondary structure transition from ß-sheet to α-helix, with GB addition, signifies a more compact protein configuration, less susceptible to salinity fluctuations. Electrochemical analyses, including cyclic voltammetry (CV) and differential pulse voltammetry (DPV), reveal GB's role in promoting the release of exogenous electron shuttles, such as flavins and c-type cytochromes (c-Cyts). The enhancement in DPV peak areas (QDPV) with GB addition implies an increase in available extracellular electron transfer sites. This investigation advances our comprehension of microbial adaptation mechanisms to salinity through EPS modifications facilitated by GB in saline habitats.

The synergistic effect of periodate/ferrate (VI) system on disinfection of antibiotic resistant bacteria and removal of antibiotic resistant genes: The dominance of Fe (IV)/Fe (V).

The proliferation of antibiotic resistant genes (ARGs) and antibiotic resistant bacteria (ARB) caused by antibiotic abuse has raised concerns about the global infectious-disease crisis. This study employed periodate (PI)/ferrate (VI) (Fe (VI)) system to disinfect Gram-negative ARB (Escherichia coli DH5α) and Gram-positive bacteria (Bacillus subtilis ATCC6633). The PI/Fe (VI) system could inactivate 1 × 108 CFU/mL of Gram-negative ARB and Gram-positive bacteria by 4.0 and 2.8 log in 30 min. Neutral and acidic pH, increase of PI dosage and Fe (VI) dosage had positive impacts on the inactivation efficiency of ARB, while alkaline solution and the coexistence of 10 mM Cl-, NO3-, SO42- and 20 mg/L humic acid had slightly negative impacts. The reactive species generated by PI/Fe (VI) system could disrupt the integrity of cell membrane and wall, leading to oxidative stress and lipid peroxidation. Intracellular hereditary substance, including DNA and ARGs (tetA), would leak into the external environment through damaged cells and be degraded. The electron spin resonance analysis and quenching experiments indicated that Fe (IV)/Fe (V) played a leading role in disinfection. Meanwhile, PI/Fe (VI) system also had an efficient removal effect on sulfadiazine, which was expected to inhibit the ARGs transmission from the source.

Comparative genomics of N-acetyl-5-methoxytryptamine members in four Prunus species with insights into bud dormancy and abiotic stress responses in Prunus avium.

KEY MESSAGE: This study provides novel insights into the evolution, diversification, and functions of melatonin biosynthesis genes in Prunus species, highlighting their potential role in regulating bud dormancy and abiotic stresses. The biosynthesis of melatonin (MEL) in plants is primarily governed by enzymatic reactions involving key enzymes such as serotonin N-acetyltransferase (SNAT), tryptamine 5-hydroxylase (T5H), N-acetylserotonin methyltransferase (ASMT) and tryptophan decarboxylase (TDC). In this study, we analyzed Melatonin genes in four Prunus species such as Prunus avium (Pavi), Prunus pusilliflora (Ppus), Prunus serulata (Pser), and Prunus persica (Pper) based on comparative genomics approach. Among the four Prunus species, a total of 29 TDCs, 998 T5Hs, 16 SNATs, and 115 ASMTs within the genome of four Prunus genomes. A thorough investigation of melatonin-related genes was carried out using systematic biological methods and comparative genomics. Through phylogenetic analysis, orthologous clusters, Go enrichment, syntenic relationship, and gene duplication analysis, we discovered both similarities and variations in Melatonin genes among these Prunus species. Additionally, our study revealed the existence of unique subgroup members in the Melatonin genes of these species, which were distinct from those found in Arabidopsis genes. Furthermore, the transcriptomic expression analysis revealed the potential significance of melatonin genes in bud dormancy regulation and abiotic stresses. Our extensive results offer valuable perspectives on the evolutionary patterns, intricate expansion, and functions of PavMEL genes. Given their promising attributes, PavTDCs, PavT5H, PavNAT, and three PavASMT genes warrant in-depth exploration as prime candidates for manipulating dormancy in sweet cherry. This was done to lay the foundation for future explorations into the structural and functional aspects of these factors in Prunus species. This study offers significant insights into the functions of ASMT, SNAT, T5H, and TDC genes and sheds light on their roles in Prunus avium. Moreover, it established a robust foundation for further exploration functional characterization of melatonin genes in fruit species.

PS2MS: A Deep Learning-Based Prediction System for Identifying New Psychoactive Substances Using Mass Spectrometry.

The rapid proliferation of new psychoactive substances (NPS) poses significant challenges to conventional mass-spectrometry-based identification methods due to the absence of reference spectra for these emerging substances. This paper introduces PS2MS, an AI-powered predictive system designed specifically to address the limitations of identifying the emergence of unidentified novel illicit drugs. PS2MS builds a synthetic NPS database by enumerating feasible derivatives of known substances and uses deep learning to generate mass spectra and chemical fingerprints. When the mass spectrum of an analyte does not match any known reference, PS2MS simultaneously examines the chemical fingerprint and mass spectrum against the putative NPS database using integrated metrics to deduce possible identities. Experimental results affirm the effectiveness of PS2MS in identifying cathinone derivatives within real evidence specimens, signifying its potential for practical use in identifying emerging drugs of abuse for researchers and forensic experts.

Horticulture crop under pressure: Unraveling the impact of climate change on nutrition and fruit cracking.

Climate change is increasingly affecting the nutritional content and structural integrity of horticultural crops, leading to challenges such as diminished fruit quality and the exacerbation of fruit cracking. This manuscript systematically explores the multifaceted impacts of these changes, with a particular focus on the nutritional quality and increased incidence of fruit cracking. An exhaustive review of current research identifies the critical role of transcription factors in mediating plant responses to climatic stressors, such as drought, temperature extremes, and saline conditions. The significance of transcription factors, including bHLH, bZIP, DOF, MDP, HD-ZIP, MYB, and ERF4, is highlighted in the development of fruit cracking, underscoring the genetic underpinnings behind stress-related phenotypic outcomes. The effectiveness of greenhouse structures in mitigating adverse climatic effects is evaluated, offering a strategic approach to sustain crop productivity amidst CO2 fluctuations and water scarcity, which are shown to influence plant physiology and lead to changes in fruit development, nutrient dynamics, and a heightened risk of cracking. Moreover, the manuscript delves into advanced breeding strategies and genetic engineering techniques, such as genome editing, to enhance crop resilience against climatic challenges. It also discusses adaptation strategies vital for sustainable horticulture, emphasizing the need to integrate novel genetic insights with controlled environment horticulture to counteract climate change's detrimental effects. The synthesis presented here underscores the urgent need for innovative breeding strategies aimed at developing resilient crop varieties that can withstand climatic uncertainty while preserving nutritional integrity.

Evaluation of emergency drills effectiveness by center of disease prevention and control staff in Heilongjiang Province, China: an empirical study using the logistic-ISM model.

Introduction: Emergency drills are critical practices that can improve the preparedness for crisis situations. This study aims to comprehend the evaluation of emergency drill effectiveness by the staff at the Centers for Disease Control and Prevention (CDC) in Heilongjiang Province, China. It identifies potential factors that could influence the personnel's appraisal of outcomes throughout the emergency drill procedure. Methods: A cross-sectional survey was conducted among public health professionals from various CDCs in Heilongjiang, a northeastern Chinese province. The binary logistic regression analysis identified the factors associated with the CDC staff's assessment of emergency drill efficacy, while the Interpretative Structural Modeling (ISM) elucidated the hierarchical structure among the influencing factors. Results: 53.3% (95% CI = 50.6-55.4) of participants perceived the emergency drills' effectiveness as low. Binary logistic regression analysis revealed that the following adverse factors associated with the emergency drills increased the risk of a lower evaluation: lack of equipment and poor facilities (OR = 2.324, 95% CI = 1.884-2.867), poor training quality (OR = 1.765, 95% CI = 1.445-2.115), low leadership focus (OR = 1.585, 95% CI = 1.275-1.971), insufficient training frequency (OR = 1.539, 95% CI = 1.258-1.882), low skill in designing emergency drill plans (OR = 1.494, 95% CI = 1.180-1.890), lack of funding (OR = 1.407, 95% CI = 1.111-1.781), and poor coordination between departments (OR = 1.335, 95% CI = 1.085-1.641). The ISM revealed the hierarchical relationship of the influential factors, which were classified into three levels: Surface, Middle and Bottom. The Surface Level factors were training frequency, training quality, leaders' focus, and inter-departmental coordination. The Middle Level factors were equipment availability and skill in designing emergency drill plans. The Bottom Level factor was funding guarantee. Discussion: This survey revealed that over half of the CDC staff rated the effectiveness of public health emergency drills as low. The Logistic-ISM Model results indicated that the evaluation of drill effectiveness was negatively influenced by insufficient facility and equipment support, financial constraints, lack of departmental coordination, and inadequate leadership attention. Among these factors, funding guarantee was the most fundamental one. Therefore, this calls for strategic decisions to increase funding for equipment, leadership training support, and effective emergency coordination.

Preparation of Aminated Sodium Lignosulfonate and Efficient Adsorption of Methyl Blue Dye.

The aminated sodium lignosulfonate (AELS) was prepared through a Mannich reaction and characterized via FT-IR, TG, SEM and XPS in this study. Subsequently, the adsorption capacity of AELS for methyl blue (MB) was evaluated under various conditions such as pH, adsorbent dosage, contact time, initial concentration and temperature. The adsorption kinetics, isotherms and thermodynamics of AELS for methyl blue were investigated and analyzed. The results were found to closely adhere to the pseudo-second-order kinetic model and Langmuir isotherm model, suggesting a single-molecular-layer adsorption process. Notably, the maximum adsorption capacity of AELS for methyl blue (153.42 mg g-1) was achieved under the specified conditions (T = 298 K, MAELS = 0.01 g, pH = 6, VMB = 25 mL, C0 = 300 mg L-1). The adsorption process was determined to be spontaneous and endothermic. Following five adsorption cycles, the adsorption capacity exhibited a minimal reduction from 118.99 mg g-1 to 114.33 mg g-1, indicating good stability. This study contributes to the advancement of utilizing natural resources effectively and sustainably.

Mechanical enhancement and high linearity health monitoring of composite materials based on CNTs/PSF/PI film sensor with ultra-low SWCNTs doping content.

A new type of embedded composite material health monitoring nano-sensor is designed to ensure that the unique material advantages of nanofillers can be maximized. The carbon nanotubes (CNTs)/polysulfone (PSF)/polyimide (PI) thin film sensor in this paper is obtained by the self-assembly of a PSF/PI asymmetric porous membrane which is prepared by a phase inversion method through vacuum filtration of SWCNTs. It is a new structure for a practical CNT sensor that can take into account both 'composite health monitoring and damage warning' and 'composite mechanical enhancement'. The new structure of the CNTs/PSF/PI film sensor is divided into two parts. The upper part consists of small-aperture finger-like holes filled with SWCNTs (the SWCNT content is 0.0127 mg cm-2). The lower part consists of large-aperture cavities conducive to resin infiltration, which enhance the interface bonding force between the sensor and the composite material. This unique structure allows the CNTs/PSF/PI film sensor to change the influence of the embedded sensor from 'introducing defects' to 'local enhancement', and the mechanical strength of the enhanced specimen can reach up to 1.68 times that of the original specimen, and the service interval can reach 2.01 times that of the original specimen. In addition, the CNTs/PSF/PI film sensor also has good sensitivity (GF = 2.54) and extremely high linearity (R2 = 0.9995), and has excellent follow-up and interface bonding ability. It can also maintain excellent fatigue resistance and stability over 46 500 vibration cycles, which provides new research ideas and research methods for the field of composite-life monitoring sensors.

Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor.

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Polyacetylenes from Saposhnikovia divaricata and their anticancer activity.

Nine polyacetylenes, including five new compounds named sadivaethynes E-I (1-5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1-5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1-2, 4-5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC50 value of 11.66 µM against HEPG2.

An autophagy-associated diagnostic signature based on peripheral blood for antibody-mediated rejection in renal transplantation.

BACKGROUND: Antibody-mediated rejection (ABMR) emerged as a major cause of graft loss in renal transplantation. Needle biopsy is the gold standard for diagnosis of ABMR in renal allografts. Thus, noninvasive diagnosis methods of ABMR with high accuracy are urgently needed to prevent unnecessary biopsies. METHODS: We collected peripheral blood transcriptome data from two independent renal transplantation cohorts with patients with ABMR, stable well-functioning transplants (STA), and T-cell mediated rejection (TCMR). Differentially expressed genes (DEGs) were identified by comparing the ABMR group with the STA group. In addition, functional enrichment analysis and gene set enrichment analysis were performed to seek new key underlying mechanisms in ABMR. Subsequently, we utilized a Boruta algorithm and least absolute shrinkage and selection operator logistic algorithm to establish a diagnostic model which was then evaluated and validated in an independent cohort. RESULTS: According to functional enrichment analysis, autophagy was found to be the primary upregulated biological process in ABMR. Based on algorithms, three autophagy-associated genes, ubiquitin specific peptidase 33 (USP33), Ras homolog mTORC1 binding (RHEB), and ABL proto-oncogene 2 (ABL2), were selected to establish the diagnostic model in the training cohort. This autophagy-related gene model possessed good diagnostic value in distinguishing ABMR from STA blood samples in the training cohort (AUC = 0.907) and in the validation cohort (AUC = 0.972). In addition, this model also showed good discernibility in distinguishing ABMR from TCMR in the training and validation cohorts (AUCs = 0.908 and 0.833). CONCLUSION: We identified and validated an autophagy-associated diagnostic model with high accuracy for renal transplant patients with ABMR. Our study provided a new potential test for the non-invasive diagnosis of ABMR in clinical practice and highlighted the importance of autophagy in ABMR.

Hypoxia-induced miR-5100 promotes exosome-mediated activation of cancer-associated fibroblasts and metastasis of head and neck squamous cell carcinoma.

The invasion-metastasis cascade in head and neck squamous cell carcinoma (HNSCC) is predominantly caused by the interaction between tumor cells and tumor microenvironment, including hypoxia as well as stromal cells. However, the mechanism of hypoxia-activated tumor-stroma crosstalk in HNSCC metastasis remains to be deciphered. Here, we demonstrated that HIF1α was upregulated in HNSCC specimens compared with adjacent normal tissues, whose overexpression was associated with lymph node metastasis and predicted unfavorable prognosis. HIF1α expression correlated positively with the levels of miR-5100 as well as α-SMA, the marker of CAFs. Hypoxia/HIF1α regulated transcriptionally miR-5100 to promote the degradation of its target gene QKI, which acts as a tumor suppressor in HNSCC. Hypoxic HNSCC-derived exosomal miR-5100 promoted the activation of CAFs by orchestrating QKI/AKT/STAT3 axis, which further facilitated HNSCC metastasis. Additionally, miR-5100 derived from plasma exosomes indicated HNSCC malignant progression. In conclusion, our findings illuminate a novel HIF1α/miR-5100/QKI pathway in HNSCC metastasis, and suggest that miR-5100 might be a potential biomarker and therapeutic target for HNSCC.

A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens.

The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (RUP4) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe3+) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that RUP4 is active against both Klebsiella pneumoniae and Acinetobacter baumannii, with this activity being dependent on direct Fe3+ chelation and enhanced under Fe3+-limiting conditions. Genetic deletion studies in K. pneumoniae reveal that RUP4 gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that RUP4 exhibits bactericidal synergy against K. pneumoniae when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting ß-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe3+-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.