A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.

KRAS mutant cancer, characterized by the activation of a plethora of phosphorylation signaling pathways, remains a major challenge for cancer therapy. Despite recent advancements, a comprehensive profile of the proteome and phosphoproteome is lacking. This study provides a proteomic and phosphoproteomic landscape of 43 KRAS mutant cancer cell lines across different tissue origins. By integrating transcriptomics, proteomics, and phosphoproteomics, we identify three subsets with distinct biological, clinical, and therapeutic characteristics. The integrative analysis of phosphoproteome and drug sensitivity information facilitates the identification of a set of drug combinations with therapeutic potentials. Among them, we demonstrate that the combination of DOT1L and SHP2 inhibitors is an effective treatment specific for subset 2 of KRAS mutant cancers, corresponding to a set of TCGA clinical tumors with the poorest prognosis. Together, this study provides a resource to better understand KRAS mutant cancer heterogeneity and identify new therapeutic possibilities.

Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Intelligent leaching rare earth elements from waste fluorescent lamps.

Rare earth elements (REEs), one of the global key strategic resources, are widely applied in electronic information and national defense, etc. The sharply increasing demand for REEs leads to their overexploitation and environmental pollution. Recycling REEs from their second resources such as waste fluorescent lamps (WFLs) is a win-win strategy for REEs resource utilization and environmental production. Pyrometallurgy pretreatment combined with acid leaching is proven as an efficient approach to recycling REEs from WFLs. Unfortunately, due to the uncontrollable components of wastes, many trials were required to obtain the optimal parameters, leading to a high cost of recovery and new environmental risks. This study applied machine learning (ML) to build models for assisting the leaching of six REEs (Tb, Y, Eu, La, and Gd) from WFLs, only needing the measurement of particle size and composition of the waste feed. The feature importance analysis of 40 input features demonstrated that the particle size, Mg, Al, Fe, Sr, Ca, Ba, and Sb content in the waste feed, the pyrometallurgical and leaching parameters have important effects on REEs leaching. Furthermore, their influence rules on different REEs leaching were revealed. Finally, some verification experiments were also conducted to demonstrate the reliability and practicality of the model. This study can quickly get the optimal parameters and leaching efficiency for REEs without extensive optimization experiments, which significantly reduces the recovery cost and environmental risks. Our work carves a path for the intelligent recycling of strategic REEs from waste.

ALKBH5 governs human endoderm fate by regulating the DKK1/4-mediated Wnt/ß-catenin activation.

N6-methyladenonsine (m6A) is ubiquitously distributed in mammalian mRNA. However, the precise involvement of m6A in early development has yet to be fully elucidated. Here, we report that deletion of the m6A demethylase ALKBH5 in human embryonic stem cells (hESCs) severely impairs definitive endoderm (DE) differentiation. ALKBH5-/- hESCs fail to undergo the primitive streak (PS) intermediate transition that precedes endoderm specification. Mechanistically, we show that ALKBH5 deficiency induces m6A hypermethylation around the 3' untranslated region (3'UTR) of GATA6 transcripts and destabilizes GATA6 mRNA in a YTHDF2-dependent manner. Moreover, GATA6 binds to the promoters of critical regulatory genes involved in Wnt/ß-catenin signaling transduction, including the canonical Wnt antagonist DKK1 and DKK4, which are unexpectedly repressed upon the dysregulation of GATA6 mRNA metabolism. Remarkably, DKK1 and DKK4 both exhibit a pleiotropic effect in modulating the Wnt/ß-catenin cascade and guard the endogenous signaling activation underlying DE formation as potential downstream targets of the ALKBH5-GATA6 regulation. Here, we unravel a role of ALKBH5 in human endoderm formation in vitro by modulating the canonical Wnt signaling logic through the previously unrecognized functions of DKK1/4, thus capturing a more comprehensive role of m6A in early human embryogenesis.

Serological response and immune-related adverse events following COVID-19 vaccination in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

With the popularity of Coronavirus disease 2019 (COVID-19) vaccine and the development of vaccination strategies, the impact of COVID-19 vaccine on cancer patients receiving immune checkpoint inhibitors (ICIs) is still unclear. In the systematic review and meta-analysis of patients with ICIs, we assessed the serological response of cancer patients receiving COVID-19 vaccine, and explored the risk of immune related adverse events (irAEs). We searched PubMed, EMBASE and Cochrane Library as of 10 June 2023, and included cancer patients who received ICIs and COVID-19 vaccine. The systematic review and meta-analysis include cohort study, cross-sectional study and case report. The outcome included the serological response, Spike-specific T-cell response, irAEs and rare adverse events. When possible, the data were analysed by random effect analysis, and the statistical heterogeneity was assessed by Q-test and I2 statistics. We explored the sources of heterogeneity through L'Abbe plots, Galbraith radial plots, and sensitivity analysis. The publication bias was evaluated by Egger's, Begg's linear regression test and funnel plot, and the impact of publication bias was further analysed by trim and fill method. 27 studies were eligible (19 cohort studies, 1 cross-sectional study and 7 case reports), involving 8331 patients (with 4724 receiving ICIs). Most studies used mRNA vaccine (BNT162b2 or mRNA-1273). Compared with cancer patients receiving chemotherapy, cancer patients receiving ICIs were significantly more likely to have seroconversion (RR = 1.05, 95%CI 1.01-1.10, P = 0.02). There were no statistically significant differences in seroconversion rates when comparing cancer patients receiving ICIs with controls without cancer (RR = 0.95, 95% CI 0.89-1.01, P = 0.09) or with cancer patients receiving targeted therapy (RR = 1.05, 95% CI 0.79-1.39, P = 0.75). The incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was (21.96%, 95%CI 16.66%-28.94%) and (14.88%, 95%CI 8.65%-25.57%), respectively. The most common irAEs were endocrine abnormalities, skin disorders, etc. The certainty of evidence was low in cancer patients with ICIs, compared with those receiving chemotherapy, and very low versus controls without cancer. Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs.

Placental ischemia-upregulated angiotensin II type 1 receptor in hypothalamic paraventricular nucleus contributes to hypertension in rat.

Preeclampsia (PE) is associated with increased angiotensin II sensitivity and poor neurological outcomes marked by temporal loss of neural control of blood pressure. Yet the role of centrally expressed angiotensin II type 1 receptor (AT1R) within the paraventricular nucleus of the hypothalamus (PVN) in the PE model is not understood. In a PE rat model with reduced placental perfusion pressure (RUPP) induced on gestational day 14 (GD14), the PVN expression and cellular localization of AT1R were assessed using immunofluorescence and western blotting. The sensitivity of RUPP to acute angiotensin II infusion was assessed. AT1R was antagonized by losartan (100 µg/kg/day) for 5 days intracerebroventricularly (ICV). Hemodynamic data and samples were collected on GD19 for further analysis. RUPP upregulated (p < 0.05) mRNA and protein of AT1R within the PVN and lowered (p < 0.05) circulating angiotensin II in rats. RUPP increased neural and microglial activation. Cellular localization assessment revealed that AT1R was primarily expressed in neurons and slightly in microglia and astrocytes. Infusion of 100 ng/kg as bolus increased the mean arterial pressure (MAP in mmHg) in both RUPP and Sham. ICV losartan infusion attenuated RUPP-increased MAP (113.6 ± 6.22 in RUPP vs. 92.16 ± 5.30 in RUPP + Los, p = 0.021) and the expression of nuclear transcription factor NF-κB, tyrosine hydroxylase (TH), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS) in the PVN. Our data suggest that centrally expressed AT1R, within the PVN, contributes to placental ischemia-induced hypertension in RUPP rats highlighting its therapeutic potential in PE.

Profiling cortical morphometric similarity in perinatal brains: Insights from development, sex difference, and inter-individual variation.

The topological organization of the macroscopic cortical networks important for the development of complex brain functions. However, how the cortical morphometric organization develops during the third trimester and whether it demonstrates sexual and individual differences at this particular stage remain unclear. Here, we constructed the morphometric similarity network (MSN) based on morphological and microstructural features derived from multimodal MRI of two independent cohorts (cross-sectional and longitudinal) scanned at 30-44 postmenstrual weeks (PMW). Sex difference and inter-individual variations of the MSN were also examined on these cohorts. The cross-sectional analysis revealed that both network integration and segregation changed in a nonlinear biphasic trajectory, which was supported by the results obtained from longitudinal analysis. The community structure showed remarkable consistency between bilateral hemispheres and maintained stability across PMWs. Connectivity within the primary cortex strengthened faster than that within high-order communities. Compared to females, male neonates showed a significant reduction in the participation coefficient within prefrontal and parietal cortices, while their overall network organization and community architecture remained comparable. Furthermore, by using the morphometric similarity as features, we achieved over 65 % accuracy in identifying an individual at term-equivalent age from images acquired after birth, and vice versa. These findings provide comprehensive insights into the development of morphometric similarity throughout the perinatal cortex, enhancing our understanding of the establishment of neuroanatomical organization during early life.

Chloroplast SRP54 and FtsH protease coordinate thylakoid membrane-associated proteostasis in Arabidopsis.

Thylakoid membrane protein quality control (PQC), which requires the coordination of membrane protein translocation and degradation of unassembled proteins, determines chloroplast development during de-etiolation. Despite numerous efforts, the regulation of this process in land plants is largely unknown. Here, we report the isolation and characterization of pale green Arabidopsis4 (pga4) mutants in Arabidopsis (Arabidopsis thaliana) with defects in chloroplast development during de-etiolation. Map-based cloning and complementation assays confirmed that PGA4 encodes the chloroplast Signal Recognition Particle 54 kDa (cpSRP54) protein. A heterogeneous Light-Harvesting Chlorophyll a/b Binding-Green Fluorescent Protein (LhcB2-GFP) fusion protein was generated as an indicative reporter for cpSRP54-mediated thylakoid translocation. LhcB2-GFP was dysfunctional and degraded to a short-form dLhcB2-GFP during de-etiolation through an N-terminal degradation initiated on thylakoid membranes. Further biochemical and genetic evidence demonstrated that the degradation of LhcB2-GFP to dLhcB2-GFP was disrupted in pga4 and yellow variegated2 (var2) mutants caused by mutations in the Filamentous Temperature-Sensitive H2 (VAR2/AtFtsH2) subunit of thylakoid FtsH. The yeast two-hybrid assay showed that the N-terminus of LhcB2-GFP interacts with the protease domain of VAR2/AtFtsH2. Moreover, the over-accumulated LhcB2-GFP in pga4 and var2 formed protein aggregates, which were insoluble in mild nonionic detergents. Genetically, cpSRP54 is a suppressor locus for the leaf variegation phenotype of var2. Together, these results demonstrate the coordination of cpSRP54 and thylakoid FtsH in maintaining thylakoid membrane PQC during the assembly of photosynthetic complexes and provide a trackable substrate and product for monitoring cpSRP54-dependent protein translocation and FtsH-dependent protein degradation.

Crystal structural effects on up/down-conversion luminescence properties of GdInO3:Tm,Yb perovskite phosphors for effective dual-mode anti-counterfeit applications.

Developing advanced luminescent materials that are recognizable under specified conditions provides better opportunity for reliable optical anti-counterfeiting techniques. In this work, to the best of our knowledge, novel GdInO3:Tm,Yb perovskite phosphors with ultrafine sizes and rounded morphologies were successfully synthesized by a facile chemical precipitation route. Two-type perovskites with orthorhombic and hexagonal structures could be obtained by calcining the precursor at 850 and 1100 °C, respectively. Under 980 nm excitation, the two phosphors exhibited cyan-bluish emission at ∼460-565 nm, red emission at 645-680 nm, and near-infrared emission at 770-825 nm arising from 1G4 + 1D2→3H5,6, 3F2,3→3H6, and 3H4→3H6 transitions of Tm3+, respectively, where the hexagonal perovskite phosphor had relatively strong and sharp red emission as well as red-shifted cyan-bluish emission via successive cross relaxations. The Yb3+ sensitizer enhanced the upconversion luminescence via effective Yb3+→Tm3+ energy transfer and the optimal Yb3+ concentrations were 10 at.% for orthorhombic perovskite and 5 at.% for hexagonal one. The upconversion mechanism mainly ascribed to two-photon processes while three-photon was also present. Upon excitation at 254 nm, their down-conversion spectra exhibited broad multibands in the wavelength range of 400-500 nm deriving from combined effects of the defect-induced emission of GdInO3 and the 1D2→3F4 + 4G4→3H6 emissions of Tm3+. The energy transfer from GdInO3 defect level to Tm3+ excitation state was observed for the first time. The unclonable security codes prepared by screen printing from those dual-mode emitting perovskite phosphors were almost invisible under natural light, which had promising potential for anti-counterfeiting application.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing.

Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.

Early warning and predicting of COVID-19 using zero-inflated negative binomial regression model and negative binomial regression model.

BACKGROUND: It is difficult to detect the outbreak of emergency infectious disease based on the exiting surveillance system. Here we investigate the utility of the Baidu Search Index, an indicator of how large of a keyword is in Baidu's search volume, in the early warning and predicting the epidemic trend of COVID-19. METHODS: The daily number of cases and the Baidu Search Index of 8 keywords (weighted by population) from December 1, 2019 to March 15, 2020 were collected and analyzed with times series and Spearman correlation with different time lag. To predict the daily number of COVID-19 cases using the Baidu Search Index, Zero-inflated negative binomial regression was used in phase 1 and negative binomial regression model was used in phase 2 and phase 3 based on the characteristic of independent variable. RESULTS: The Baidu Search Index of all keywords in Wuhan was significantly higher than Hubei (excluded Wuhan) and China (excluded Hubei). Before the causative pathogen was identified, the search volume of "Influenza" and "Pneumonia" in Wuhan increased with the number of new onset cases, their correlation coefficient was 0.69 and 0.59, respectively. After the pathogen was public but before COVID-19 was classified as a notifiable disease, the search volume of "SARS", "Pneumonia", "Coronavirus" in all study areas increased with the number of new onset cases with the correlation coefficient was 0.69 ~ 0.89, while "Influenza" changed to negative correlated (rs: -0.56 ~ -0.64). After COVID-19 was closely monitored, the Baidu Search Index of "COVID-19", "Pneumonia", "Coronavirus", "SARS" and "Mask" could predict the epidemic trend with 15 days, 5 days and 6 days lead time, respectively in Wuhan, Hubei (excluded Wuhan) and China (excluded Hubei). The predicted number of cases would increase 1.84 and 4.81 folds, respectively than the actual number of cases in Wuhan and Hubei (excluded Wuhan) from 21 January to 9 February. CONCLUSION: The Baidu Search Index could be used in the early warning and predicting the epidemic trend of COVID-19, but the search keywords changed in different period. Considering the time lag from onset to diagnosis, especially in the areas with medical resources shortage, internet search data can be a highly effective supplement of the existing surveillance system.

Inequities in human papillomavirus vaccination among children aged 9-14 years old under constrained vaccine supply in China.

BACKGROUND: Inequities in access to human papillomavirus (HPV) vaccine are becoming a growing critical issue globally. Few studies investigate the factors determining HPV vaccine uptake disparities when vaccine supply is constrained, especially in low- and middle-income countries. The aim of this study was to investigate inequities of HPV vaccination and related factors under the constrained vaccine supply in China. METHODS: A cross-sectional survey was conducted in a developed eastern coastal province and a developing western one in China between November and December 2022. Employing multistage stratified cluster random sampling, the study collected data from parents of children aged 9-14. Mixed-effects logistic regression models with school units as random effects were used for analysis. RESULTS: From 4,127 eligible parents (as vaccine decision makers for girls), 1,346 (32.6%) intended to vaccinate their daughters against HPV, of which 836 (62.1%) attempted to schedule a vaccination appointment. Only 16.4% succeeded in booking an appointment. More than half of the intended parents expected the imported 9-valent HPV vaccine. There were significant disparities in HPV vaccine awareness, intention, and vaccination behavior across educational, income, geographic, ethnic, gender, and health literacy levels. Vaccine awareness and intentions were higher among parents with higher socioeconomic status; however, girls from lower socioeconomic families were more likely to receive the HPV vaccine and had a higher domestically produced vaccination rate. Significant disparities exist in vaccination intentions and actual vaccination behaviors, primarily due to large supply constraints of the HPV vaccine. CONCLUSIONS: Sustained health education campaigns are needed to raise awareness of the HPV vaccine, improve health literacy, and decrease over-preference for the 9-valent HPV vaccine. A mother's HPV vaccination behavior was positively associated with increased intention and actual vaccination behavior for her daughter. This study advocates for complementary cervical cancer prevention programs targeting both mothers and daughters.

Prediction of drug-induced hepatotoxicity based on histopathological whole slide images.

Liver is an important metabolic organ in human body and is sensitive to toxic chemicals or drugs. Adverse reactions caused by drug hepatotoxicity will damage the liver and hepatotoxicity is the leading cause of removal of approved drugs from the market. Therefore, it is of great significance to identify liver toxicity as early as possible in the drug development process. In this study, we developed a predictive model for drug hepatotoxicity based on histopathological whole slide images (WSI) which are the by-product of drug experiments and have received little attention. To better represent the WSIs, we constructed a graph representation for each WSI by dividing it into small patches, taking sampled patches as nodes and calculating the correlation coefficients between node features as the edges of the graph structure. Then a WSI-level graph convolutional network (GCN) was built to effectively extract the node information of the graph and predict the toxicity. In addition, we introduced a gated attention global context vector (gaGCV) to combine the global context to make node features to contain more comprehensive information. The results validated on rat liver in vivo data from the Open TG-GATES show that the use of WSI for the prediction of toxicity is feasible and effective.

Myocardial contrast echocardiography evaluation of coronary microvascular dysfunction to Predict MACEs in patients with heart failure with preserved ejection fraction follow-up.

BACKGROUND: CMD refers to the abnormalities of the tiny arteries and capillaries within the coronary artery system, which result in restricted or abnormal blood flow. CMD is an important mechanism involved in ischemic heart disease and secondary heart failure. CMD can explain left ventricular dysfunction and poor prognosis.The European Association of Cardiovascular Imaging recommends the use of MCE for the assessment of myocardial perfusion. Myocardial contrast echocardiography (MCE) is used to evaluate the accuracy of Coronary microvascular dysfunction (CMD) for predicting major adverse cardiac events (MACEs) in patients with heart failure with preserved ejection fraction (HFpEF) at follow-up. METHODS: The clinical data of 142 patients diagnosed with HFpEF in our hospital from January 2020 to January 2022 were retrospectively summarized and stratified into 77 cases (> 1) in the CMD group and 65 cases (= 1) in the non-CMD group based on the perfusion score index (PSI) of the 17 segments of the left ventricle examined by the admission MCE, and the perfusion parameters were measured at the same time, including the peak plateau intensity (A value), the curve slope of the curve rise (ßvalue) and A × ß values. At a median follow-up of 27 months till October 2023, MACEs were recorded mainly including heart failure exacerbation, revascularization, cardiac death, etc. RESULTS: Increasing age, hypertension, diabetes, and coronary artery disease in the CMD group resulted in decreased left ventricular ejection fraction (LVEF), increased plasma NT-B-type natriuretic peptide (BNP) and left ventricular global longitudinal strain (LVGLS), decreased A-values and A × ß-values, and an increased incidence of MACEs (P < 0.05). Univariate and multivariate Cox regression analyses showed that LVGLS (HR = 1.714, 95% CI = 1.289-2.279, P < 0.001) and A × ß values (HR = 0.636, 95% CI = 0.417 to 0.969, P = 0.035) were independent predictors of MACEs in patients with HFpEF. The receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) of LVGLS combined with A × ß value for diagnosis of MACEs was 0.861 (95% CI = 0.761 ~ 0.961, P < 0.001), which was significantly higher than that of LVGLS or A × ß value (P < 0.05). The Kaplan-Meier survival curves showed that the cumulative survival rate in CMD group was significantly lower than non-CMD group (logrank χ2 = 6.626, P = 0.010), with the most significant difference at 20 months of follow-up. CONCLUSION: MCE can evaluate CMD semi-quantitatively and quantitatively, LVGLS combined with A × ß value has good performance in predicting the risk of developing MACEs in patients with HFpEF at 3 years of follow-up, and CMD can be used as an important non-invasive indicator for assessing clinical prognosis.

Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Identification and Fungicide Sensitivity of Fusarium spp. Associated with Root Rot of Scutellaria baicalensis in Shanxi Province, China.

Fusarium root rot is usually classified as an extremely destructive soilborne disease. From 2020 to 2021, Fusarium root rot was observed in production areas and seriously affected the yield and quality of Scutellaria baicalensis in Shanxi Province, China. Based on morphological characteristics and combined analysis of the internal transcribed spacer region of ribosomal DNA and translation elongation factor 1-alpha sequences, 68 Fusarium isolates obtained in this work were identified as F. oxysporum (52.94%), F. acuminatum (20.59%), F. solani (16.17%), F. proliferatum (5.88%), F. incarnatum (2.94%), and F. brachygibbosum (1.47%). In the pathogenicity tests, all Fusarium isolates could infect S. baicalensis roots, presenting different pathogenic ability. Among these isolates, F. oxysporum was found to have the highest virulence on S. baicalensis roots, followed by F. acuminatum, F. solani, F. proliferatum, F. brachygibbosum, and F. incarnatum. According to fungicide sensitivity tests, Fusarium isolates were more sensitive to fludioxonil and difenoconazole, followed by carbendazim, thiophanate-methyl, and hymexazol. In brief, this is the first report of Fusarium species (F. oxysporum, F. acuminatum, F. solani, F. proliferatum, F. incarnatum, and F. brachygibbosum) as causal agents of root rot of S. baicalensis in Shanxi Province, China. The fungicide sensitivity results will be helpful for formulating management strategies of S. baicalensis root rot.

Role of radiomics in staging liver fibrosis: a meta-analysis.

BACKGROUND: Fibrosis has important pathoetiological and prognostic roles in chronic liver disease. This study evaluates the role of radiomics in staging liver fibrosis. METHOD: After literature search in electronic databases (Embase, Ovid, Science Direct, Springer, and Web of Science), studies were selected by following precise eligibility criteria. The quality of included studies was assessed, and meta-analyses were performed to achieve pooled estimates of area under receiver-operator curve (AUROC), accuracy, sensitivity, and specificity of radiomics in staging liver fibrosis compared to histopathology. RESULTS: Fifteen studies (3718 patients; age 47 years [95% confidence interval (CI): 42, 53]; 69% [95% CI: 65, 73] males) were included. AUROC values of radiomics for detecting significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4) were 0.91 [95%CI: 0.89, 0.94], 0.92 [95%CI: 0.90, 0.95], and 0.94 [95%CI: 0.93, 0.96] in training cohorts and 0.89 [95%CI: 0.83, 0.91], 0.89 [95%CI: 0.83, 0.94], and 0.93 [95%CI: 0.91, 0.95] in validation cohorts, respectively. For diagnosing significant fibrosis, advanced fibrosis, and cirrhosis the sensitivity of radiomics was 84.0% [95%CI: 76.1, 91.9], 86.9% [95%CI: 76.8, 97.0], and 92.7% [95%CI: 89.7, 95.7] in training cohorts, and 75.6% [95%CI: 67.7, 83.5], 80.0% [95%CI: 70.7, 89.3], and 92.0% [95%CI: 87.8, 96.1] in validation cohorts, respectively. Respective specificity was 88.6% [95% CI: 83.0, 94.2], 88.4% [95% CI: 81.9, 94.8], and 91.1% [95% CI: 86.8, 95.5] in training cohorts, and 86.8% [95% CI: 83.3, 90.3], 94.0% [95% CI: 89.5, 98.4], and 88.3% [95% CI: 84.4, 92.2] in validation cohorts. Limitations included use of several methods for feature selection and classification, less availability of studies evaluating a particular radiological modality, lack of a direct comparison between radiology and radiomics, and lack of external validation. CONCLUSION: Although radiomics offers good diagnostic accuracy in detecting liver fibrosis, its role in clinical practice is not as clear at present due to comparability and validation constraints.

Co-inoculation of Soybean Seedling with Trichoderma asperellum and Irpex laceratus Promotes the Absorption of Nitrogen and Phosphorus.

Soybean are one of the main oil crops in the world. The study demonstrated that co-inoculation with Trichoderma asperellum (Sordariomycetes, Hypocreomycetidae) and Irpex laceratus (Basidiomycota, Polyporales) isolated from Kosteletzkya virginica can promote the growth of soybean seedlings. The two fungi were found to produce various enzymes, including cellulase, amylase, laccase, protease, and urease. Upon inoculation, T. asperellum mainly colonized within the phloem of the roots in soybean seedlings, while I. laceratus mainly in the xylem and phloem of the roots. Physiological parameters, such as plant height, root length, and fresh weight, were significantly increased in soybean seedlings co-inoculated with T. asperellum and I. laceratus. Moreover, the expression of key genes related to N and P absorption and metabolism was also increased, leading to improved N and P utilization efficiency in soybean seedlings. These results indicate that the two fungi may have complementary roles in promoting plant growth, co-inoculation with T. asperellum and I. laceratus can enhance the growth and nutrient uptake of soybean. These findings suggest that T. asperellum and I. laceratus have the potential to be used as bio-fertilizers to improve soybean growth and yield.

Parkinson's disease with anxiety: clinical characteristics and their correlation with oxidative stress, inflammation, and pathological proteins.

OBJECTIVE: This study was performed to explore the differences in the clinical characteristics and oxidative stress indicators, inflammatory factors, and pathological proteins in serum between Parkinson's disease (PD) with anxiety (PD-A) and with no anxiety (PD-NA) patients, and further correlations among clinical characteristics and above variables were analyzed in PD-A and PD-NA groups. METHODS: A total of 121 patients with PD were enrolled in this study and assessed by the Hamilton Anxiety Scale (14 items) (HAMA-14). These patients were divided into PD-A and PD-NA groups according to a cut-off point of 7 of HAMA-14. Demographic variables were collected, and clinical symptoms were assessed by multiple rating scales. The levels of free radicals, inflammatory factors, and pathological proteins in serum were measured by chemical colorimetric method and enzyme-linked immunosorbent assay (ELISA). The differences of above variables were compared between PD-A and PD-NA groups, and the correlations of clinical symptoms with the abovevariables were analyzed in PD-A and PD-NA groups. RESULTS: The frequency of PD-A was 62.81%. PD-A group exhibited significantly impaired motor dysfunction and multiple non-motor symptoms, including fatigue, sleep behavior disorder, restless leg syndrome and autonomic dysfunction, and dramatically compromised activities of daily living compard with PD-NA group. PD-A group displayed prominently increasedlevels of hydroxyl radical (·OH) and tumor necrosis factor (TNF)-α, and a decreased nitric oxide (NO) level in serum compared with PD-NA group (P<0.001, P = 0.001, P= 0.027, respectively). ·OH, NO, and TNF-α were identified as the risk factors of PD-A (OR = 1.005, P = 0.036; OR = 0.956, P = 0.017; OR = 1.039, P = 0.033, respectively). In PD patients, HAMA-14 score was significantly and positively correlated with the levels of ·OH and TNF-α in serum (P<0.001, P = 0.002, respectively). In PD-A group, ·OH level was significantly and negatively correlated with Aß1-42 level, while TNF-α level was significantly and positively correlated with P-tau (S396) level in serum. CONCLUSIONS: The frequency of PD-A is high. PD-A patients present more severe motor dysfunction and multiple non-motor symptoms, and poorer activities of daily living. The increased levels of ·OH and TNF-α levels and the decreased NO level in serum are all associated with more severe anxiety in PD patients.Findings from this study may provide in-depth insights into the clinical characteristics, underlying mechanisms of PD-A, and potential correlations among anxiety, oxidative stress, inflammation, and cognitive decline in PD patients.