NASTRA: accurate analysis of short tandem repeat markers by nanopore sequencing with repeat-structure-aware algorithm.

Short-tandem repeats (STRs) are the type of genetic markers extensively utilized in biomedical and forensic applications. Due to sequencing noise in nanopore sequencing, accurate analysis methods are lacking. We developed NASTRA, an innovative tool for Nanopore Autosomal Short Tandem Repeat Analysis, which overcomes traditional database-based methods' limitations and provides a precise germline analysis of STR genetic markers without the need for allele sequence reference. Demonstrating high accuracy in cell line authentication testing and paternity testing, NASTRA significantly surpasses existing methods in both speed and accuracy. This advancement makes it a promising solution for rapid cell line authentication and kinship testing, highlighting the potential of nanopore sequencing for in-field applications.

Effect of electromagnetic middle-ear implant simulating sites on the stapes spatial motion: A finite element analysis.

The electromagnetic middle-ear implant (MEI) is a new type of hearing device for addressing sensorineural and mixed hearing loss. The hearing compensation effect of the MEI varies depending on the transducer stimulation sites. This paper investigates the impact of transducer stimulation sites on MEI performance by analyzing stapes spatial motion. Firstly, we constructed a human-ear finite element model based on micro-CT scanning and inverse molding techniques. This model was validated by comparing its predictions of stapes spatial motion and cochlear response with experimental data. Then, stimulation force was applied at four common sites: umbo, incus body, incus long process and stapes to simulate the electromagnetic transducer. Results show that at low and middle frequencies, stapes-stimulating and incus-long-process-stimulating produce similar spatial motion to normal hearing; at high frequencies, incus-body-stimulating produces similar results to normal hearing. The equivalent sound pressure level generated by the stapes piston motion is less sensitive to the stimulation direction than that deduced by the stapes rocking motion.

Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment.

Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is the dominant hydrolase of 2',3'-cyclic GMP-AMP (cGAMP). Inhibition of ENPP1 contributes to increased cGAMP concentration and stimulator of interferon gene (STING) activation, with the potential to boost immune response against cancer. ENPP1 is a promising therapeutic target in tumor immunotherapy. To date, orally bioavailable ENPP1 inhibitors with highly potent activity under physiological conditions have been rarely reported. Herein, we report our effort in the design and synthesis of two different series of ENPP1 inhibitors, and in the identification of a highly potent ENPP1 inhibitor 27 (IC50 = 1.2 nM at pH 7.5), which significantly enhanced the cGAMP-mediated STING activity in THP-1 cells. Phosphonate compound 27 has good preclinical pharmacokinetic profiles with low plasma clearance rate in mouse, rat, and dog. It has been developed as bis-POM prodrug 36 which successfully improves the oral bioavailability of 27. In the Pan02 syngeneic mouse model of pancreatic cancer, orally administered 36 showed synergistic effect in combination with radiotherapy.

Estimating epidemic trajectories of SARS-CoV-2 and influenza A virus based on wastewater monitoring and a novel machine learning algorithm.

The COVID-19 pandemic has altered the circulation of non-SARS-CoV-2 respiratory viruses. In this study, we carried out wastewater surveillance of SARS-CoV-2 and influenza A virus (IAV) in three key port cities in China through real-time quantitative PCR (RT-qPCR). Next, a novel machine learning algorithm (MLA) based on Gaussian model and random forest model was used to predict the epidemic trajectories of SARS-CoV-2 and IAV. The results showed that from February 2023 to January 2024, three port cities experienced two waves of SARS-CoV-2 infection, which peaked in late-May and late-August 2023, respectively. Two waves of IAV were observed in the spring and winter of 2023, respectively with considerable variations in terms of onset/offset date and duration. Furthermore, we employed MLA to extract the key features of epidemic trajectories of SARS-CoV-2 and IAV from February 3rd, to October 15th, 2023, and thereby predicted the epidemic trends of SARS-CoV-2 and IAV from October 16th, 2023 to April 22nd, 2024, which showed high consistency with the observed values. These collective findings offer an important understanding of SARS-CoV-2 and IAV epidemics, suggesting that wastewater surveillance together with MLA emerges as a powerful tool for risk assessment of respiratory viral diseases and improving public health preparedness.

Comparison of Different Deodorizing Treatments on the Flavor of Paddy Field Carp, Analyzed by the E-Nose, E-Tongue and Gas Chromatography-Ion Mobility Spectrometry.

Changes in the flavor and taste profiles of Paddy Field Carp after deodorization with perilla juice (PJ), cooking wine (CW) and a mixture of the two (PJ-CW) were analyzed using the E-nose, E-tongue, gas chromatography-ion mobility spectrometry (GC-IMS), free amino acid analysis and taste nucleotide analysis. The E-nose and E-tongue revealed that deodorization reduced the content of sulfur-containing compounds, enhanced umami, bitterness, sourness and astringency, and decreased saltiness. PCA and OPLS-DA analysis successfully distinguished between the effects of the treatments. Free amino acids increased from 8777.67 to 11,125.98 mg/100 g and umami amino acids increased from 128.24 to 150.37 mg/100 g after PJ-CW deodorization (p < 0.05). Equivalent umami concentration (EUC) comparisons showed that PJ-CW treatment produced the greatest synergistic umami enhancement (to 3.15 g MSG equiv./100 g). GC-IMS detected 52 aroma compounds; PJ treatment produced the greatest diversity of aldehydes, including heptanal, nonanal, hexanal, 3-methylbutanal, (E)-2-heptenal and (E,E)-2,4-heptadienal. The total content of volatile flavor compounds was the highest after PJ-CW treatment, and the content of many characteristic flavor substances (3-hydroxy-2-butanone, benzaldehyde, 5-methyl-2(3H)-furanone) increased. These findings provided a theoretical basis for the further development of deodorization methods for Paddy Field Carp.

Enhanced machine learning approaches for OSA patient screening: model development and validation study.

Age, gender, body mass index (BMI), and mean heart rate during sleep were found to be risk factors for obstructive sleep apnea (OSA), and a variety of methods have been applied to predict the occurrence of OSA. This study aimed to develop and evaluate OSA prediction models using simple and accessible parameters, combined with multiple machine learning algorithms, and integrate them into a cloud-based mobile sleep medicine management platform for clinical use. The study data were obtained from the clinical records of 610 patients who underwent polysomnography (PSG) at the Sleep Medicine Center of the Second Affiliated Hospital of Fujian Medical University between January 2021 and December 2022. The participants were randomly divided into a training-test group (80%) and an independent validation group (20%). The logistic regression, artificial neural network, naïve Bayes, support vector machine, random forest, and decision tree algorithms were used with age, gender, BMI, and mean heart rate during sleep as predictors to build a risk prediction model for moderate-to-severe OSA. To evaluate the performance of the models, we calculated the area under the receiver operating curve (AUROC), accuracy, recall, specificity, precision, and F1-score for the independent validation set. In addition, the calibration curve, decision curve, and clinical impact curve were generated to determine clinical usefulness. Age, gender, BMI, and mean heart rate during sleep were significantly associated with OSA. The artificial neural network model had the best efficacy compared with the other prediction algorithms. The AUROC, accuracy, recall, specificity, precision, F1-score, and Brier score were 80.4% (95% CI 76.7-84.1%), 69.9% (95% CI 69.8-69.9%), 86.5% (95% CI 81.6-91.3%), 61.5% (95% CI 56.6-66.4%), 53.2% (95% CI 47.7-58.7%), 65.9% (95% CI 60.2-71.5%), and 0.165, respectively, for the artificial neural network model. The AUROCs for the LR, NB, SVM, RF, and DT models were 80.2%, 79.7%, 79.2%, 78.4%, and 70.4%, respectively. The six models based on four simple and easily accessible parameters effectively predicted moderate-to-severe OSA in patients with PSG screening, with the artificial neural network model having the best performance. These models can provide a reliable tool for early OSA diagnosis, and their integration into a cloud-based mobile sleep medicine management platform could improve clinical decision making.

A retrospective study on the impact of radiotherapy on the survival outcomes of small cell lung cancer patients based on the SEER database.

Small cell lung cancer (SCLC) patients exhibit significant heterogeneity in tumor burden, physical condition, and responses to initial treatment. This diversity in treatment responses can result in varying treatment outcomes. The primary objective of this study was to explore the patient demographics associated with improved survival outcomes through radiotherapy. Based on the SEER database, we identified 42,824 SCLC patients enrolled between 2004 and 2015. These patients were stratified into radiotherapy (n = 20,360) and non-radiotherapy groups (n = 22,464). We controlled for confounding factors using propensity score matching (PSM) analysis. Subsequently, Kaplan-Meier (KM) analysis was employed to evaluate the impact of radiotherapy on patients' overall survival (OS) and cancer-specific survival (CSS). Cancer-specific mortality was further analyzed using competitive risk models. Cox analysis was also conducted to examine additional variables potentially affecting the survival of SCLC patients. We identified a total of 42,824 eligible patients, and following PSM, 13,329 patients were successfully matched in both the radiotherapy and non-radiotherapy groups. The KM analysis showed that the median OS was 9 months in the radiotherapy group and 6 months in the non-radiotherapy group. The median CSS was 10 months in the radiotherapy group and 7 months in the non-radiotherapy group. The 5-year OS and 10-year OS rates were 6.2% versus 1.6% in the radiotherapy group and 2.6% versus 0.8% in the non-radiotherapy group (P < 0.001). Competitive risk analysis showed that cancer-specific mortality was significantly higher in the non-radiotherapy group than in the radiotherapy group (P < 0.001). Multivariate Cox analysis showed that the radiotherapy group (relative non-radiotherapy group) showed a significant positive effect on survival outcomes (OS: HR 0.658 95% CI [0.642, 0.675] P < 0.001; CSS: HR 0.662 95% CI [0.645, 0.679], P < 0.001). In addition, age, gender, race, primary tumor site, T stage, N stage, M stage, chemotherapy, and surgery were also considered as important predictors of SCLC outcome. The results of the subgroup analysis showed that the radiotherapy group showed a significant survival advantage regardless of age, sex, race, primary tumor site, M stage, chemotherapy, and surgery (P < 0.001). Radiotherapy may improve both OS and CSS in SCLC patients. Patients with SCLC may benefit from radiotherapy regardless of age, sex, race, primary tumor site, M stage, chemotherapy, and surgery.

Enhanced Mineralization of Organic Pollutants through Atomic Hydrogen-Mediated Alternative Transformation Pathways.

Electrocatalytic hydrogen atom-hydroxyl radical (H*-·OH) redox system is a promising approach for contaminant removal and mineralization. However, its working mechanism, especially the effect of H*, remains unclear, hindering its practical application. Herein, we constructed an electrochemical reactor equipped with our self-made Pd-loaded Ti/TiO2 nanotube cathode and a commercial boron-doped diamond anode. After fulfilling the electrode characterization and free radical detection, we employed coumarin and 7-azido-4-methylcoumarin as probes to confirm the participation of H* in the transformation of organic compounds. A comprehensive study on the degradation kinetics, reaction, and mineralization mechanisms using benzoic acid (BA) and 4-chlorophenol (4-CP) as model compounds was further conducted. The rate constants and total organic carbon removal of BA and 4-CP in the redox system increased compared with those of the individual oxidation and reduction processes. Theoretical calculations demonstrate that H* opens up alternative pathways for BA and 4-CP ring cleavage, forming quinones as reactive intermediates. Furthermore, H* facilitates the mineralization of the typical intermediates, maleic acid and fumaric acid, through C=C bond addition and H-abstraction from the 1,1-diol structure. The presence of H* provides alternative pathways for pollutant transformation, consequently reducing the treatment duration.

Coordinated molecular and ecological adaptations underlie a highly successful parasitoid.

The success of an organism depends on the molecular and ecological adaptations that promote its beneficial fitness. Parasitoids are valuable biocontrol agents for successfully managing agricultural pests, and they have evolved diversified strategies to adapt to both the physiological condition of hosts and the competition of other parasitoids. Here, we deconstructed the parasitic strategies in a highly successful parasitoid, Trichopria drosophilae, which parasitizes a broad range of Drosophila hosts, including the globally invasive species D. suzukii. We found that T. drosophilae had developed specialized venom proteins that arrest host development to obtain more nutrients via secreting tissue inhibitors of metalloproteinases (TIMPs), as well as a unique type of cell-teratocytes-that digest host tissues for feeding by releasing trypsin proteins. In addition to the molecular adaptations that optimize nutritional uptake, this pupal parasitoid has evolved ecologically adaptive strategies including the conditional tolerance of intraspecific competition to enhance parasitic success in older hosts and the obligate avoidance of interspecific competition with larval parasitoids. Our study not only demystifies how parasitoids weaponize themselves to colonize formidable hosts but also provided empirical evidence of the intricate coordination between the molecular and ecological adaptations that drive evolutionary success.

Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors.

SOS1, a guanine nucleotide exchange factor (GEF), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status, and represents a promising new drug target to treat all KRAS-driven tumors. Herein, we employed a scaffold hopping strategy to design, synthesize, and optimize a series of novel binary ring derivatives as SOS1 inhibitors. Among them, compound 10f (HH0043) displayed potent activities in both biochemical and cellular assays and favorable pharmacokinetic profiles. Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a subcutaneous KRAS G12C-mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%). On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project.

Bioinformatic analysis and identification of macrophage polarization-related genes in intervertebral disc degeneration.

BACKGROUND: The relationship between macrophage polarization-related genes (MPRGs) and intervertebral disc degeneration (IDD) is unclear. The purpose of this study was to identify biomarkers associated with IDD. METHODS: Three transcriptome sequencing datasets, GSE124272, GSE70362 and GSE56081 were included in this study. Differential expressed genes (DEGs) were obtained by overlapping DEGs1 from the GSE124272 and DEGs2 from the GSE70362. The key module genes associated with the score of MPRGs were identified by weighted gene co-expression network analysis (WGCNA) in GSE12472. Differentially expressed (DE)-MPRGs were acquired by overlapping key module genes and DEGs. Candidate genes were obtained by SVM-RFE algorithm. Biomarkers were obtained by expression level analysis. In addition, immune analysis, enrichment analysis and construction of a ceRNA network were completed. The blood samples from 9 IDD patients (IDD group) and 9 healthy individuals (Control group) were used to verify the expression levels of these biomarkers through RT-qPCR. RESULTS: A sum of 39 DEGs were obtained by overlapping DEGs1 and DEGs2, and 1,633 key module genes were obtained by WGCNA. 9 DE-MPRGs were obtained by overlapping DEGs and key module genes, and ST6GALNAC2, SMIM3, and IFITM2 were identified as biomarkers. These biomarkers were enriched in KEGG_RIBOSOME pathway. Check-point, Cytolytic_activity, T_cell_co-stimulation, Neutrophils, Th2_cells and TIL differed between IDD and control groups. Some relationships such as SMIM3-hsa-miR-107-LINC02381 were identified in the network. Moreover, the functional analysis results of biomarkers showed that FITM2 and SMIM3 could predict IDD and nociceptive pain. The RT-qPCR showed that ST6GALNAC2 and IFITM2 were significantly expressed in IDD group in contrast to the control group. CONCLUSION: The macrophage polarization related biomarkers (ST6GALNAC2, SMIM3 and IFITM2) were associated with IDD, among which IFITM2 could be considered as a key gene for IDD. This may provide a new direction for the biological treatment and mechanism research into IDD.

Evaluation of the therapeutic effect of Sacha inchi oil in atopic dermatitis mice.

Atopic dermatitis (AD) is a prevalent inflammatory skin condition characterized by a multifaceted pathogenesis, which encompasses immune system signaling dysregulation, compromised skin barrier function, and genetic influencers. Sacha inchi (Plukenetia volubilis L.) oil (SIO) has demonstrated potent anti-inflammatory and antioxidant properties, however, the mechanism underlying the beneficial effects of SIO on AD remains unclear. This study aims to investigate the anti-AD effect of SIO and its possible molecular mechanism in mice with AD. The results demonstrated that SIO significantly reduced the degree of skin lesions and scratching, and improved the skin thickness and mast cell infiltration in AD mice. Furthermore, SIO significantly reduced the levels of immunoglobulin E, histamine and thymic stromal lymphopoietin in serum of AD mice. Additionally, it inhibited the expression of tumor necrosis factor-γ, interferon-γ, interleukin-2, interleukin-4, interleukin 1ß and other inflammatory cytokines in the lesions skin of mice. The Western blotting analysis revealed that SIO exhibited an upregulatory effect on the protein expression of filaggrin and loricrin, while concurrently exerting inhibitory effects on the protein expression and phosphorylation levels of P38, ERK, NF-κB, and IκBα within their respective signaling pathways. Consequently, it can be inferred that SIO exerts a significant anti-atopic dermatitis effect by modulating the P38, ERK, NF-κB, and IκBα signaling pathways. This study contributes to expand the research and development potential of SIO, and provides novel insights and potential therapeutic strategies for AD treatment.

Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities.

White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.

Role of the Yersinia pestis phospholipase D (Ymt) in the initial aggregation step of biofilm formation in the flea.

Transmission of Yersinia pestis by fleas depends on the formation of condensed bacterial aggregates embedded within a gel-like matrix that localizes to the proventricular valve in the flea foregut and interferes with normal blood feeding. This is essentially a bacterial biofilm phenomenon, which at its end stage requires the production of a Y. pestis exopolysaccharide that bridges the bacteria together in a cohesive, dense biofilm that completely blocks the proventriculus. However, bacterial aggregates are evident within an hour after a flea ingests Y. pestis, and the bacterial exopolysaccharide is not required for this process. In this study, we characterized the biochemical composition of the initial aggregates and demonstrated that the yersinia murine toxin (Ymt), a Y. pestis phospholipase D, greatly enhances rapid aggregation following infected mouse blood meals. The matrix of the bacterial aggregates is complex, containing large amounts of protein and lipid (particularly cholesterol) derived from the flea's blood meal. A similar incidence of proventricular aggregation occurred after fleas ingested whole blood or serum containing Y. pestis, and intact, viable bacteria were not required. The initial aggregation of Y. pestis in the flea gut is likely due to a spontaneous physical process termed depletion aggregation that occurs commonly in environments with high concentrations of polymers or other macromolecules and particles such as bacteria. The initial aggregation sets up subsequent binding aggregation mediated by the bacterially produced exopolysaccharide and mature biofilm that results in proventricular blockage and efficient flea-borne transmission. IMPORTANCE: Yersinia pestis, the bacterial agent of plague, is maintained in nature in mammal-flea-mammal transmission cycles. After a flea feeds on a mammal with septicemic plague, the bacteria rapidly coalesce in the flea's digestive tract to form dense aggregates enveloped in a viscous matrix that often localizes to the foregut. This represents the initial stage of biofilm development that potentiates transmission of Y. pestis when the flea later bites a new host. The rapid aggregation likely occurs via a depletion-aggregation mechanism, a non-canonical first step of bacterial biofilm development. We found that the biofilm matrix is largely composed of host blood proteins and lipids, particularly cholesterol, and that the enzymatic activity of a Y. pestis phospholipase D (Ymt) enhances the initial aggregation. Y. pestis transmitted by flea bite is likely associated with this host-derived matrix, which may initially shield the bacteria from recognition by the host's intradermal innate immune response.

Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas.

Endobronchial leiomyomas are rare benign neoplasms of the lungs that arise from the smooth muscle cells of the bronchi and bronchioles. While surgical resection is the mainstay of treatment for these tumors, bronchoscopic interventional therapies are also effective and can help preserve lung function in certain cases. A 40-year-old male patient presented with a persistent cough and sputum production for over 4 months. A chest computed tomography scan revealed nodular lesions in the lower lobe bronchus, later confirmed as an endobronchial leiomyoma. The patient refused surgical intervention and opted for minimally invasive bronchoscopic treatments, including electric snare resection, argon plasma coagulation, and balloon dilation, resulting in a successful outcome with no recurrence during follow-up. Clinicians should consider bronchoscopic interventions as a viable treatment option for endobronchial leiomyomas patients who are either ineligible for surgical resection or opt not to undergo surgery.

The genomic history and global migration of a windborne pest.

Many insect pests, including the brown planthopper (BPH), undergo windborne migration that is challenging to observe and track. It remains controversial about their migration patterns and largely unknown regarding the underlying genetic basis. By analyzing 360 whole genomes from around the globe, we clarify the genetic sources of worldwide BPHs and illuminate a landscape of BPH migration showing that East Asian populations perform closed-circuit journeys between Indochina and the Far East, while populations of Malay Archipelago and South Asia undergo one-way migration to Indochina. We further find round-trip migration accelerates population differentiation, with highly diverged regions enriching in a gene desert chromosome that is simultaneously the speciation hotspot between BPH and related species. This study not only shows the power of applying genomic approaches to demystify the migration in windborne migrants but also enhances our understanding of how seasonal movements affect speciation and evolution in insects.

Nicotine improves DSS-induced colitis by inhibiting NLRP3 and altering gut microbiota.

Ulcerative colitis (UC) is a chronic recurrent inflammatory disease affecting the rectum and colon. Numerous epidemiological studies have identified smoking as a protective factor for UC. Dysbiosis of intestinal microbiota and release of inflammatory factors are well-established characteristics associated with UC. Therefore, we have observed that nicotine exhibits the potential to ameliorate colitis symptoms in UC mice. Additionally, it exerts a regulatory effect on colonic microbiota dysbiosis by promoting the growth of beneficial bacteria while suppressing harmful bacteria. Combined in vivo and in vitro investigations demonstrate that nicotine primarily impedes the assembly of NLRP3, subsequently inhibiting downstream IL-1ß secretion.

Occurrence, fate, and risk assessment of antibiotics in conventional and advanced drinking water treatment systems: From source to tap.

The occurrence and removal of 38 antibiotics from nine classes in two drinking water treatment plants (WTPs) were monitored monthly over one year to evaluate the efficiency of typical treatment processes, track the source of antibiotics in tap water and assess their potential risks to ecosystem and human health. In both source waters, 18 antibiotics were detected at least once, with average total antibiotic concentrations of 538.5 ng/L in WTP1 and 569.3 ng/L in WTP2. The coagulation/flocculation and sedimentation, sand filtration and granular activated carbon processes demonstrated limited removal efficiencies. Chlorination, on the other hand, effectively eliminated antibiotics by 48.7 ± 11.9%. Interestingly, negative removal was observed along the distribution system, resulting in a significant antibiotic presence in tap water, with average concentrations of 131.5 ng/L in WTP1 and 362.8 ng/L in WTP2. Source tracking analysis indicates that most antibiotics in tap water may originate from distribution system. The presence of antibiotics in raw water and tap water posed risks to the aquatic ecosystem. Untreated or partially treated raw water could pose a medium risk to infants under six months. Water parameters, for example, temperature, total nitrogen and total organic carbon, can serve as indicators to estimate antibiotic occurrence and associated risks. Furthermore, machine learning models were developed that successfully predicted risk levels using water quality parameters. Our study provides valuable insights into the occurrence, removal and risk of antibiotics in urban WTPs, contributing to the broader understanding of antibiotic pollution in water treatment systems.

REMIMAZOLAM IMPROVES THE MARKERS OF POSTRESUSCITATION CEREBRAL INJURY IN A SWINE MODEL OF CARDIAC ARREST.

ABSTRACT: Introduction: Previous studies have manifested that those sedatives acting on γ-aminobutyric acid A (GABAa) receptor could produce effective brain protection against regional and global ischemic stimulation. The present study was designed to investigate the effect of a novel GABAa receptor agonist, remimazolam postconditioning (RP) on cerebral outcome after global ischemic stimulation induced by cardiac arrest and resuscitation in swine. Methods: A total of 24 swine were used in this study, in which the animals were randomly divided into the following three groups: sham group (n = 6), cardiopulmonary resuscitation (CPR) group (n = 9), and CPR + RP group (n = 9). The experimental model was established by the procedure of 10 min of cardiac arrest and 5 min of CPR. Those resuscitated swine in the CPR + RP group received an intravenous infusion of 2.5 mg/kg of remimazolam within 60 min. Postresuscitation cerebral injury biomarkers and neurological function were evaluated for a total of 24 h. At 24 h after resuscitation, brain cortex was harvested to evaluate the severity of pathologic damage, including tissue inflammation, oxidative stress, apoptosis, and necroptosis. Results: Baseline characteristics and CPR outcomes were not significantly different between the CPR and CPR + RP groups. After resuscitation, significantly greater cerebral injury and neurological dysfunction were observed in the CPR and CPR + RP groups than in the sham group. However, remimazolam postconditioning significantly alleviated cerebral injury and improved neurological dysfunction after resuscitation when compared with the CPR group. At 24 h after resuscitation, tissue inflammation, oxidative stress, and cell apoptosis and necroptosis were significantly increased in the CPR and CPR + RP groups when compared with the sham group. Nevertheless, the severity of pathologic damage mentioned previously were significantly milder in those swine treated with the remimazolam when compared with the CPR group. Conclusions: In a swine model of cardiac arrest and resuscitation, the remimazolam administered after resuscitation significantly improved the markers of postresuscitation cerebral injury and therefore protected the brain against global ischemic stimulation.

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae.

Fungal meroterpenoids are diverse structurally intriguing molecules with various biological properties. One large group within this compound class is derived from the aromatic precursor 3,5-dimethylorsellinic acid (DMOA). In this study, we constructed engineered metabolic pathways in the fungus Aspergillus oryzae to expand the molecular diversity of meroterpenoids. We employed the 5-methylorsellinic acid (5-MOA) synthase FncE and three additional biosynthetic enzymes for the formation of (6R,10'R)-epoxyfarnesyl-5-MOA methyl ester, which served as a non-native substrate for four terpene cyclases from DMOA-derived meroterpenoid pathways. As a result, we successfully generated six unnatural 5-MOA-derived meroterpenoid species, demonstrating the effectiveness of our approach in the generation of structural analogues of meroterpenoids.