Massively parallel combination screen reveals small molecule sensitization of antibiotic-resistant Gram-negative ESKAPE pathogens.

Antibiotic resistance, especially in multidrug-resistant ESKAPE pathogens, remains a worldwide problem. Combination antimicrobial therapies may be an important strategy to overcome resistance and broaden the spectrum of existing antibiotics. However, this strategy is limited by the ability to efficiently screen large combinatorial chemical spaces. Here, we deployed a high-throughput combinatorial screening platform, DropArray, to evaluate the interactions of over 30,000 compounds with up to 22 antibiotics and 6 strains of Gram-negative ESKAPE pathogens, totaling to over 1.3 million unique strain-antibiotic-compound combinations. In this dataset, compounds more frequently exhibited synergy with known antibiotics than single-agent activity. We identified a compound, P2-56, and developed a more potent analog, P2-56-3, which potentiated rifampin (RIF) activity against Acinetobacter baumannii and Klebsiella pneumoniae. Using phenotypic assays, we showed P2-56-3 disrupts the outer membrane of A. baumannii. To identify pathways involved in the mechanism of synergy between P2-56-3 and RIF, we performed genetic screens in A. baumannii. CRISPRi-induced partial depletion of lipooligosaccharide transport genes (lptA-D, lptFG) resulted in hypersensitivity to P2-56-3/RIF treatment, demonstrating the genetic dependency of P2-56-3 activity and RIF sensitization on lpt genes in A. baumannii. Consistent with outer membrane homeostasis being an important determinant of P2-56-3/RIF tolerance, knockout of maintenance of lipid asymmetry complex genes and overexpression of certain resistance-nodulation-division efflux pumps - a phenotype associated with multidrug-resistance - resulted in hypersensitivity to P2-56-3. These findings demonstrate the immense scale of phenotypic antibiotic combination screens using DropArray and the potential for such approaches to discover new small molecule synergies against multidrug-resistant ESKAPE strains.

Adsorption Behaviors and Mechanism of Phenol and Catechol in Wastewater by Magnetic Graphene Oxides: A Comprehensive Study Based on Adsorption Experiments, Mathematical Models, and Molecular Simulations.

This study provides a comprehensive analysis of the adsorption behaviors and mechanisms of phenol and catechol on magnetic graphene oxide (MGO) nanocomposites based on adsorption experiments, mathematical models, and molecular simulations. Through systematic experiments, the influence of various parameters, including contact time, pH conditions, and ionic strength, on the adsorption efficacy was comprehensively evaluated. The optimal contact time for adsorption was identified as 60 min, with the observation that an increase in inorganic salt concentration adversely affected the MGOs' adsorption capacity for both phenol and catechol. Specifically, MGOs exhibited a superior adsorption performance under mildly acidic conditions. The adsorption isotherm was well represented by the Langmuir model, suggesting monolayer coverage and finite adsorption sites for both pollutants. In terms of adsorption kinetics, a pseudo-first-order kinetic model was the most suitable for describing phenol adsorption, while catechol adsorption conformed more closely to a pseudo-second-order model, indicating distinct adsorption processes for these two similar compounds. Furthermore, this research utilized quantum chemical calculations to decipher the interaction mechanisms at the molecular level. Such calculations provided both a visual representation and a quantitative analysis of the interactions, elucidating the underlying physical and chemical forces governing the adsorption phenomena. The findings could not only offer crucial insights for the treatment of coal industrial wastewater containing phenolic compounds with bridging macroscopic observations with microscopic theoretical explanations but also advance the understanding of material-pollutant interactions in aqueous environments.

Concentrations, Sources and Health Risk Assessment of Polycyclic Aromatic Hydrocarbons in Chinese Herbal Medicines.

The determination and evaluation of 16 polycyclic aromatic hydrocarbons (PAHs) in seven Chinese herbal medicines (CHMs) were conducted through a rapid and straightforward extraction and purification method, coupled with GC-MS. A sample-based solid-phase extraction (SPE) pretreatment technique, incorporating isotopic internal standards, was employed for detecting various medicinal parts of CHMs. The assay exhibited linearity within the range of 5 to 500 ng/mL, with linear coefficients (R2) for PAHs exceeding 0.999. The recoveries of spiked standards ranged from 63.37% to 133.12%, with relative standard deviations (RSDs) ranging from 0.75% to 14.54%. The total PAH content varied from 176.906 to 1414.087 µg/kg. Among the 16 PAHs, phenanthrene (Phe) was consistently detected at the highest levels (47.045-168.640 µg/kg). Characteristic ratio analysis indicated that oil, coal, and biomass combustion were the primary sources of PAHs in CHMs. The health risk associated with CHMs was assessed using the lifetime carcinogenic risk approach, revealing potential health risks from the consumption of honeysuckle, while the health risks of consuming Lycium chinense berries were deemed negligible. For the other five CHMs (glycyrrhizae, Coix lacryma, ginseng, lotus seed, seed of Sterculia lychnophora), the health risk from consumption fell within acceptable ranges. Furthermore, sensitivity analyses utilizing Monte Carlo exposure assessment methods identified PAH levels in CHMs as health risk sensitizers. It is crucial to recognize that the consumption of herbal medicines is not a continuous process but entails potential health risks. Hence, the monitoring and risk assessment of PAH residues in CHMs demand careful attention.

Antidepressant effects of esketamine via the BDNF/AKT/mTOR pathway in mice with postpartum depression and their offspring.

Postpartum depression (PPD) is a serious mental health problem that can negatively affect future generations. BDNF/AKT/mTOR signaling in the frontal lobe and hippocampus in mice is associated with depression, but its role in mice with PPD and their offspring is unknown. This study was aimed at investigating the effects of esketamine (ESK), a drug approved for treatment of refractory depression, on the BDNF/AKT/mTOR pathway in mice with PPD and their offspring. A model of chronic unpredictable mild stress with pregnancy was used. ESK was injected into postpartum mice, and behavioral tests were conducted to predict the severity of symptoms at the end of lactation and in the offspring after adulthood. Both mice with PPD and their offspring showed significant anxiety- and depression-like behaviors that were ameliorated with the ESK intervention. ESK enhanced exploratory behavior in unfamiliar environments, increased the preference for sucrose, and ameliorated the impaired BDNF/AKT/mTOR signaling in the frontal and hippocampal regions in mice. Thus, ESK may have great potential in treating PPD and decreasing the incidence of depression in offspring.

Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

Spatial impacts of the intercity flow of long stay international visitors based on mobile phone data in Yangtze River Delta, China.

The intercity daily flow of long stay international visitors (LSIV) reflects the economic globalisation and regional integration of a region. We made the first attempt to use mobile phone data to identify international visitors who stayed longer than one month in the Yangtze River Delta (YRD) region in 2019, analysed the spatial patterns of LSIV, and revealed the impact factors associated with the daily intercity flow of LSIV. We discussed spatial dependence using multiscale geographically weighted regression (MGWR), and performed cluster analysis to understand the combination effects. The results show that enterprises have the largest effect, AQI and administrative hierarchy have relatively low effects, and income, imports and exports do not have any significant effect. Overall, the economically developed eastern regions of the YRD region are more attractive for daily travel by LSIV, with the Shanghai metropolitan area being the most attractive. Our findings provide new insights into the relationship between the intercity daily flow of LSIV and the urban economy and society in the delta region to help suggest planning recommendations to enhance the globalisation development strategy and provide a better environment for international visitors in the delta region.

Carcinogenic and non-carcinogenic health risk assessment of organic compounds and heavy metals in electronic cigarettes.

E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains controversial and requires further research and regulation. In this study, we aimed to understand the possible hazards to humans of four compounds (formaldehyde, acetaldehyde, acrolein, and acetone) and seven heavy metals (arsenic, cadmium, manganese, lead, copper, nickel, and chromium) contained in e-cigarette liquids and aerosols and perform a health risk assessment. We searched PubMed, CNKI, and other databases for relevant literature to obtain data on organic compounds and heavy metals in e-cigarette liquids and aerosols, and conducted acute, chronic, and carcinogenic risk assessments of various chemicals by different exposure routes. This study showed that exposure to four organic compounds and seven heavy metals in e-cigarette aerosols and e-liquids can cause varying levels of health risks in humans through different routes, with the inhalation route posing a higher overall risk than dermal exposure and oral intake. Various chemicals at high exposure doses can produce health risks beyond the acceptable range. E-cigarette designers must improve their products by changing the composition of the e-liquid and controlling the power of the device to reduce the health effects on humans.

Diagnostic performance of prediction models for extraprostatic extension in prostate cancer: a systematic review and meta-analysis.

PURPOSE: In recent decades, diverse nomograms have been proposed to predict extraprostatic extension (EPE) in prostate cancer (PCa). We aimed to systematically evaluate the accuracy of MRI-inclusive nomograms and traditional clinical nomograms in predicting EPE in PCa. The purpose of this meta-analysis is to provide baseline summative and comparative estimates for future study designs. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane databases were searched up to May 17, 2023, to identify studies on prediction nomograms for EPE of PCa. The risk of bias in studies was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). Summary estimates of sensitivity and specificity were obtained with bivariate random-effects model. Heterogeneity was investigated through meta-regression and subgroup analysis. RESULTS: Forty-eight studies with a total of 57 contingency tables and 20,395 patients were included. No significant publication bias was observed for either the MRI-inclusive nomograms or clinical nomograms. For MRI-inclusive nomograms predicting EPE, the pooled AUC of validation cohorts was 0.80 (95% CI: 0.76, 0.83). For traditional clinical nomograms predicting EPE, the pooled AUCs of the Partin table and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram were 0.72 (95% CI: 0.68, 0.76) and 0.79 (95% CI: 0.75, 0.82), respectively. CONCLUSION: Preoperative risk stratification is essential for PCa patients; both MRI-inclusive nomograms and traditional clinical nomograms had moderate diagnostic performance for predicting EPE in PCa. This study provides baseline comparative values for EPE prediction for future studies which is useful for evaluating preoperative risk stratification in PCa patients. CRITICAL RELEVANCE STATEMENT: This meta-analysis firstly evaluated the diagnostic performance of preoperative MRI-inclusive nomograms and clinical nomograms for predicting extraprostatic extension (EPE) in prostate cancer (PCa) (moderate AUCs: 0.72-0.80). We provide baseline estimates for EPE prediction, these findings will be useful in assessing preoperative risk stratification of PCa patients. KEY POINTS: • MRI-inclusive nomograms and traditional clinical nomograms had moderate AUCs (0.72-0.80) for predicting EPE. • MRI combined clinical nomogram may improve diagnostic accuracy of MRI alone for EPE prediction. • MSKCC nomogram had a higher specificity than Partin table for predicting EPE. • This meta-analysis provided baseline and comparative estimates of nomograms for EPE prediction for future studies.

The Diagnostic Performance of Tumor Stage on MRI for Predicting Prostate Cancer-Positive Surgical Margins: A Systematic Review and Meta-Analysis.

PURPOSE: Surgical margin status in radical prostatectomy (RP) specimens is an established predictive indicator for determining biochemical prostate cancer recurrence and disease progression. Predicting positive surgical margins (PSMs) is of utmost importance. We sought to perform a meta-analysis evaluating the diagnostic utility of a high clinical tumor stage (≥3) on magnetic resonance imaging (MRI) for predicting PSMs. METHOD: A systematic search of the PubMed, Embase databases, and Cochrane Library was performed, covering the interval from 1 January 2000 to 31 December 2022, to identify relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 method was used to evaluate the studies' quality. A hierarchical summary receiver operating characteristic plot was created depicting sensitivity and specificity data. Analyses of subgroups and meta-regression were used to investigate heterogeneity. RESULTS: This meta-analysis comprised 13 studies with 3924 individuals in total. The pooled sensitivity and specificity values were 0.40 (95% CI, 0.32-0.49) and 0.75 (95% CI, 0.69-0.80), respectively, with an area under the receiver operating characteristic curve of 0.63 (95% CI, 0.59-0.67). The Higgins I2 statistics indicated moderate heterogeneity in sensitivity (I2 = 75.59%) and substantial heterogeneity in specificity (I2 = 86.77%). Area, prevalence of high Gleason scores (≥7), laparoscopic or robot-assisted techniques, field strength, functional technology, endorectal coil usage, and number of radiologists were significant factors responsible for heterogeneity (p ≤ 0.01). CONCLUSIONS: T stage on MRI has moderate diagnostic accuracy for predicting PSMs. When determining the treatment modality, clinicians should consider the factors contributing to heterogeneity for this purpose.

PEG-GNPs aggravate MCD-induced steatohepatitic injury and liver fibrosis in mice through excessive lipid accumulation-mediated hepatic inflammatory damage.

Rapid development of gold nanoparticles (GNPs) in delivering pharmaceutics and therapeutics approaches still linger the concerns of their toxic effects. Nonalcoholic steatohepatitis (NASH) is characterized by excessive lipid accumulation and overt hepatic inflammatory damage, and is the leading cause of chronic liver disease worldwide. This study aimed to assess the potential hepatic effects of GNPs on NASH phenotype and progression in mice. Mice were fed a MCD diet for 8 weeks to elicit NASH and then intravenously injected with PEG-GNPs at a single dose of 1, 5, and 25 mg/kg-bw. After 24 h and 1 week of administration, the levels of plasma ALT and AST, and the number of lipid droplets, the degree of lobular inflammation and the contents of triglycerides and cholesterols in the livers of the NASH mice significantly increased compared with the untreated NASH mice, indicating that the severity of MCD diet-induced NASH-like symptoms in mice increased after PEG-GNP administration. Moreover, the aggravated hepatic steatosis in a manner involving altered expression of the genes related to hepatic de novo lipogenesis, lipolysis, and fatty acid oxidation was observed after PEG-GNP administration. Additionally, the RNA levels of biomarkers of hepatic pro-inflammatory responses, endoplasmic reticulum stress, apoptosis, and autophagy in MCD-fed mice increased compared with the untreated NASH group. Moreover, PEG-GNP-treated NASH mice displayed an increase in MCD diet-induced hepatic fibrosis, revealed by massive deposition of collagen fiber in the liver and increased expression of fibrogenic genes. Collectively, these results suggest that hepatic GNP deposition after PEG-GNP administration increase the severity of MCD-induced NASH phenotype in mice, which is attributable to, in large part, increased steatohepatitic injury and liver fibrosis in mice.

68Ga-labeled WVP peptide as a novel PET probe for molecular biological diagnosis of unstable thoracic aortic aneurysm and early dissection: an animal study.

Objective: Type IV collagen (Col-IV) is a prospective biomarker for diagnosing and treating of unstable thoracic aortic aneurysm and dissection (TAAD). This study aims to evaluate the feasibility of 68Ga-labeled WVP peptide (68Ga-DOTA-WVP) as a novel Col-IV-targeted probe for TAAD biological diagnosis using PET/CT. Methods: WVP peptide was modified with bifunctional chelator DOTA for 68Ga radiolabeling. Immunohistochemical staining was used to evaluate the expression and location of Col-IV and elastin in aortas treated with 3-aminopropionitrile fumarate (BAPN) at different time points (0, 2, and 4 weeks). The imaging performance of 68Ga-DOTA-WVP was investigated using Micro-PET/CT in a BAPN-induced TAAD mouse model. The relationship between 68Ga-DOTA-WVP uptake in aortic lesions and the serum levels of TAAD-related biomarkers including D-dimer, C-reactive protein (CRP), and serum soluble suppression of tumorigenicity-2 (sST2) was also analyzed. Results: 68Ga-DOTA-WVP was readily prepared with high radiochemical purity and stability in vitro. 68Ga-DOTA-WVP Micro-PET/CT could detect Col-IV exposure of unstable aneurysms and early dissection in BAPN-induced TAAD mice, but little 68Ga-DOTA-WVP uptake was shown in the control group at each imaging time point. The differences of Col-IV expression and distribution of 68Ga-DOTA-WVP both in TAAD and control groups further verified the imaging efficiency of 68Ga-DOTA-WVP PET/CT. Additionally, a higher sST2 level was found in the imaging positive (n = 14) than the negative (n = 8) group (9.60 ± 1.14 vs. 8.44 ± 0.52, P = 0.014). Conclusion: 68Ga-DOTA-WVP could trace the exposure and abnormal deposition of Col-IV in enlarged and early injured aortas, showing a potential for biological diagnosis, whole-body screening, and progression monitoring of TAAD.

Differentiation of placenta percreta through MRI features and diffusion-weighted magnetic resonance imaging.

OBJECTIVES: To identify whether parameters measured from diffusion kurtosis and intravoxel incoherent motion help diagnose placenta percreta. METHODS: We retrospectively enrolled 75 patients with PAS disorders including 13 patients with placenta percreta and 40 patients without PAS disorders. Each patients underwent diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM), and diffusion kurtosis imaging (DKI). The apparent diffusion coefficient (ADC), perfusion fraction (f), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), mean diffusion kurtosis (MK) and mean diffusion coefficient (MD) were measured by the volumetric analysis and compared. MRI features were also analyzed and compared. The receiver operating characteristic (ROC) curve and logistic regression analysis were used to evaluate the diagnostic efficiency of different diffusion parameters and MRI features for distinguishing placental percreta. RESULTS: D* was an independent risk factor from DWI for predicting placenta percreta with sensitivity of 73% and specificity of 76%. Focal exophytic mass remained as independent risk factor from MRI features for predicting placenta percreta with sensitivity of 72.7% and specificity of 88.1%. When the two risk factors were combined together, the AUC was the highest, 0.880 (95% CI 0.8-0.96). CONCLUSION: D* and focal exophytic mass were associated with placenta percreta. A combination of the 2 risk factors can be used to predict placenta percreta. CRITICAL RELEVANCE STATEMENT: A combination of D* and focal exophytic mass can be used to differentiate placenta percreta.

Primary malignant melanoma of the esophagus combined with squamous cell carcinoma: A case report.

BACKGROUND: Primary malignant melanoma of the esophagus is a rare malignant tumor of the esophagus, and its combination with squamous cell carcinoma is also rare. Here, we report the diagnosis and treatment of a case of primary esophageal malignant melanoma combined with squamous cell carcinoma. CASE SUMMARY: A middle-aged man underwent gastroscopy for dysphagia. Gastroscopy revealed multiple bulging esophageal lesions, and after pathologic and immunohistochemical analyses, the patient was finally diagnosed with "malignant melanoma with squamous cell carcinoma". This patient received comprehensive treatment. After one year of follow-up, the patient was in good condition, and the esophageal lesions seen on gastroscopy were controlled, but unfortunately, liver metastasis occurred. CONCLUSION: When multiple esophageal lesions are present, the possibility of multiple pathological sources should be considered. This patient was diagnosed with primary esophageal malignant melanoma combined with squamous cell carcinoma.

Effects of acupuncture on obstructive sleep apnea-hypopnea syndrome: A meta-analysis.

Our study aimed to systematically evaluate the effect of acupuncture in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). Literature search of four Chinese databases and six English databases for studies published from the inception of each database to March 1, 2022 and identify relevant studies published in Chinese or English. Related randomized controlled trials of acupuncture for the treatment of OSAHS were included to analyze the efficacy of acupuncture. Two researchers independently reviewed all of the retrieved studies to screen for eligible studies and extract the required relevant data. Included studies were subjected to a methodological quality assessment using the Cochrane Manual 5.1.0, and to a meta-analysis using Cochrane Review Manager version 5.4. A total of 19 studies with 1365 participants were examined. Compared with the control group, the apnea-hypopnea index, lowest oxygen saturation, Epworth Sleepiness Scale, interleukin-6, tumor necrosis factor α, and nuclear factor κ-B indicators all exhibited statistically significant changes. Thus, acupuncture was effective in alleviating the state of hypoxia and sleepiness and reduced the inflammatory response and disease severity among reported patients with OSAHS. Therefore, acupuncture could be widely used in the clinical treatment of OSAHS patients as a complementary strategy and warrants further study.

Association of MRI Features and Adverse Maternal Outcome in Patients With Placenta Accreta Spectrum Disorders After Abdominal Aortic Balloon Occlusion.

BACKGROUND: MRI features may be associated with adverse maternal outcome in patients with placenta accreta spectrum (PAS) disorders even with abdominal aortic balloon occlusion (AABO). PURPOSE: This study aimed to identify risk factors of MRI for association with adverse maternal outcome in patients with PAS disorders after AABO. STUDY TYPE: Retrospective. POPULATION: Clinical and MRI features of 80 patients were retrospectively reviewed from October 2016 to August 2021. A total of 40 patients had adverse maternal outcomes including intrapartum/peripartum bleeding >1000 mL and/or emergency hysterectomy after AABO. SEQUENCE: Half-Fourier acquisition single-shot turbo spin echo and gradient echo imaging True fast imaging with steady-state precession (True-FISP) at 1.5T MR scanner. ASSESSMENT: MRI features were evaluated by three radiologists and were tested for any association with adverse maternal outcome. STATISTICAL TESTS: Interobserver agreement was calculated with kappa (k) statistics. Association between MRI features and adverse maternal outcomes were evaluated by univariate and multivariate analyses. A nomogram was constructed based on the logistic regression. RESULTS: The interobserver agreement ranged from fair to substantial (k = 0.379-0.783). Multivariate analyses revealed that short cervical length (OR: 4.344), abnormal intraplacental vascularity (OR: 6.005), placental bulge (OR: 9.085), and myometrial interruption (OR: 9.550) were independent risk factors for adverse maternal outcomes. The combination of four risk factors together demonstrated the highest AUC of 0.851 (95% CI 0.769-0.933) with a sensitivity and specificity of 77.5% and 72.5%, respectively and then a nomogram composed of the above four risk factors was constructed to represent the probability of adverse maternal outcome. DATA CONCLUSION: The nomogram demonstrated the association between MRI features and patient's poor outcome after undergoing AABO and C-section delivery for PAS. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Deterministic and Probabilistic Health Risk Assessment of Toxic Metals in the Daily Diets of Residents in Industrial Regions of Northern Ningxia, China.

This study was designed to investigate the toxic metal (aluminum (Al), arsenic (As), chromium (Cr), cadmium (Cd), copper (Cu), nickel (Ni), lead (Pb), and zinc (Zn)) concentrations in drinking water and different foodstuffs meat (pork, beef, and mutton), cereals (rice, flour, corn, millet), beans (cowpeas, tofu), potatoes (potato, sweet potato), solanaceous fruits (pepper, eggplant, bitter gourd, cucumber), vegetables (cabbage, cauliflower, spinach), and fruits (apples, watermelons, pears, grapes)) and then estimate the potential health risks of toxic metal consumption to local residents in industrial regions of northern Ningxia, China. As in drinking water, Cr in meat, Pb in cereals, Pb in beans, As and Pb in potatoes, Pb in solanaceous fruits, Cr and Ni in vegetables, and Ni and Pb in fruits were the most contaminated heavy metals in the corresponding food with over-standard rates of 16.7%, 12.5%, 5.1%, 60%, 50%, 50%, 38.2%, 44.4%, 44.4%, 31.8%, and 31.8%, respectively.The results of the deterministic assessment of health risks showed that the total noncarcinogenic risk value of dietary intake of toxic metals by the local population was 5.6106, indicating that toxic metals pose a high noncarcinogenic risk. The order of the non-carcinogenic risk is HIcereal (1.2104) > HIsolanaceous fruit (0.9134) > HIVegetables (0.8726) > HIFruit (0.8170) > HIMeat (0.7269) > HIDrinking water (0.6139) > HIBeans (0.2991) > HIPotatoes (0.1573). The total carcinogenic health risk from exposure to toxic metals through dietary intake was 9.98 × 10-4, indicating that the total cancer risk value of residents is beyond the acceptable range (10-4) under the current daily dietary exposure and implies a high risk of cancer. The order of the carcinogenic risk is RDrinking water (2.34 × 10-4) > RMeat (2.11 × 10-4) > Rsolanaceous fruit (1.89 × 10-4) > RFruit (1.88 × 10-4) > Rcereal (1.36 × 10-4) > RPotatoes (2.44 × 10-5) > RVegetables (1.51 × 10-5) > RBeans (0). The probabilistic assessment results showed that 98.83% of the population is exposed to severe noncarcinogenic risk and 87.02% is exposed to unacceptable carcinogenic risk. The sensitivity analysis showed that drinking water, local cereals, vegetables, and fruits were the major contributors to health risks. Our results indicated that the daily dietary exposure of residents in industrial regions of northern Ningxia poses a serious threat to human health, and it is suggested that relevant departments should strengthen monitoring and control of the current situation of toxic metal pollution in the environment and continue to pay attention and take measures to reduce the exposure of toxic metals in the diets of residents in this area.

Two new alkaloids produced by Dothideomycetes sp. BMC-101 isolated from the Magnolia grandiflora.

AbstactA total of 16 fungal strains were isolated from fresh leaves and flowers of Magnolia grandiflora and the EtOAc extracts of them were assayed for antitumor activities. Among these, the fungus Dothideomycetes sp. BMC-101 with broad spectrum inhibition was selected for further study. Four alkaloids (1-4) including two new compounds (2-(hydroxyimino)-3-phenylpropanoyl)-L-phenylalanine (1) and 8-Acetyl-bisdethiobis(methylsulfanyl)apoaranotin (4)) were isolated from Dothideomycetes sp. BMC-101. The structure of 1 was characterized with an oxime moiety formed by the condensation of two phenylalanines. To our knowledge, this is the first report on a fungal phenylalanine derivative with an oxime moiety.

Vaginal Lactobacillus fatty acid response mechanisms reveal a novel strategy for bacterial vaginosis treatment.

Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related species, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the human vaginal microbiota and sequesters OA in a derivative form that only ohyA-harboring organisms can exploit. Finally, OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro model of BV, suggesting a novel approach for treatment.