Color-coded parametric imaging support display of vessel hemorrhage-an in vitro experiment and clinical validation study.

Background: Digital Subtraction Angiography (DSA) is currently the most effective diagnostic method for vascular diseases, but it is still subject to various factors, resulting in uncertain diagnosis. Therefore, a new technology is needed to help clinical doctors improve diagnostic accuracy and efficiency. Purpose: The objective of the study was to investigate the effect of utilizing color-coded parametric imaging techniques on the accuracy of identifying active bleeding through DSA, the widely accepted standard for diagnosing vascular disorders. Methods: Several variables can delay the diagnosis and treatment of active bleeding with DSA. To resolve this, we carried out an in vitro simulation experiment to simulate vascular hemorrhage and utilized five color-coded parameters (area under curve, time to peak, time-of-arrival, transit time, and flow rate of contrast agent) to determine the optimal color coding parameters. We then verified it in a clinical study. Results: Five different color-coded parametric imaging methods were compared and the time-of-arrival color coding was the most efficient technique for diagnosing active hemorrhage, with a statistically significant advantage (P < 0.001). In clinical study, 135 patients (101 with confirmed bleeding and 34 with confirmed no bleeding) were collected. For patients whose bleeding could not be determined using DSA alone (55/101) and whose no bleeding could not be diagnosed by DSA alone (35/55), the combination of time-of-arrival color parametric imaging was helpful for diagnosis, with a statistically significant difference (P < 0.01 and P = 0.01). Conclusions: The time-of-arrival color coding imaging method is a valuable tool for detecting active bleeding. When combined with DSA, it improves the visual representation of active hemorrhage and improves the efficiency of diagnosis.

Palladium-Catalyzed Asymmetric Desymmetrization for the Simultaneous Construction of Chiral Phosphorus and Quaternary Carbon Stereocenters.

A palladium-catalyzed asymmetric tandem Heck and carbonylation of bisallyl-phosphine oxides has been developed. This desymmetrization process provided an efficient route to the simultaneous synthesis of a chiral P-stereogenic center and a chiral quaternary carbon stereocenter in good yields with good diastereo- and enantioselectivities.

Programmable Lanthanide Metal-Organic Framework for Ultra-Efficient Nucleic Acids Extraction and Interaction Analysis.

Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.

Expanding the Structural Diversity of Tubulin-Targeting Agents: Development of Highly Potent Benzimidazoles for Treating Fungal Diseases.

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1H-benzo[d]imidazole (A25) exhibited optimal antifungal activity against Sclerotinia sclerotiorum (S. s.), affording an excellent half-maximal effective concentration (EC50) of 0.158 µg/mL, which was higher than that of the reference agent carbendazim (EC50 = 0.594 µg/mL). Pot experiments revealed that compound A25 (200 µg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A25 and ß-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1.

Hepatitis C virus (HCV) is a positive-stranded RNA virus that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV RNA genome. However, the roles of the m5C modification and its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, we demonstrate that HCV infection enhances the expression of the host m5C reader YBX1 through the transcription factor MAX. YBX1 acts as an m5C reader, recognizing the m5C-modified NS5A C7525 site in the HCV RNA genome and significantly enhancing HCV RNA stability. This m5C-modification is also required for YBX1 colocalization with lipid droplets and HCV Core protein. Moreover, YBX1 facilitates HCV RNA replication, as well as viral assembly/budding. The tryptophan residue at position 65 (W65) of YBX1 is critical for these functions. Knockout of YBX1 or the application of YBX1 inhibitor SU056 suppresses HCV RNA replication and viral protein translation. To our knowledge, this is the first report demonstrating that the interaction between host m5C reader YBX1 and HCV RNA m5C methylation facilitates viral replication. Therefore, hepatic-YBX1 knockdown holds promise as a potential host-directed strategy for HCV therapy.

Sedation-free pediatric [18F]FDG imaging on totalbody PET/CT with the assistance of artificial intelligence.

PURPOSE: While sedation is routinely used in pediatric PET examinations to preserve diagnostic quality, it may result in side effects and may affect the radiotracer's biodistribution. This study aims to investigate the feasibility of sedation-free pediatric PET imaging using ultra-fast total-body (TB) PET scanners and deep learning (DL)-based attenuation and scatter correction (ASC). METHODS: This retrospective study included TB PET (uExplorer) imaging of 35 sedated pediatric patients under four years old to determine the minimum effective scanning time. A DL-based ASC method was applied to enhance PET quantification. Both quantitative and qualitative assessments were conducted to evaluate the image quality of ultra-fast DL-ASC PET. Five non-sedated pediatric patients were subsequently used to validate the proposed approach. RESULTS: Comparisons between standard 300-second and ultra-fast 15-second imaging, CT-ASC and DL-ASC ultra-fast 15-second images, as well as DL-ASC ultra-fast 15-second images in non-sedated and sedated patients, showed no significant differences in qualitative scoring, lesion detectability, and quantitative Standard Uptake Value (SUV) (P = ns). CONCLUSIONS: This study demonstrates that pediatric PET imaging can be effectively performed without sedation by combining ultra-fast imaging techniques with a DL-based ASC. This advancement in sedation-free ultra-fast PET imaging holds potential for broader clinical adoption.

The clinicopathological features of lung metastases of parathyroid cancinoma.

Parathyroid carcinoma(PC) is an extremely rare malignant tumor of the parathyroid glands. The lung is the most common target organ for PC distant metastases. In this study, twelve patients diagnosed with PC with lung metastases were enrolled in the study. Hematoxylin and Eosin(H&E) stained, immunohistochemical stained and next-generation sequencing (NGS) of a 425-gene panel were performed on tumor tissue samples. At the same time, we also evaluated its histopathologic characteristics. The results indicate that the microscopic examination of metastatic lesions reveals the same structure and characteristics as PC; the tumor was composed of relatively uniform cells organized in nests and separated by thin fibrous bands and abundant blood vessels. Immunohistochemical evaluation of Ki67, CyclinD1, PTH, SYN, CgA, and CD56 was useful in diagnosing PC with lung metastases. The most frequently genetic alterations were mutations of CDC73 and copy number variation (CNV) of MCL1, with a mutation rate of 25 %. In addition, the mutations of CDC73, ATM, TP53, ALK, ERBB2, MAP3K4, TSC1, CCND1 and CNV of CDK4, MCL1, SMARCB1 overlap between metastatic lesions and primary lesions. In conclusions, PC is a rare endocrine malignant tumor that is very difficult to diagnose preoperatively and prone to clinical recurrence or distant metastasis. Genetic mutations, presentation and histological characteristic were the basis for diagnosing PC with lung metastases.

Gut microbiota modulating intestinal stem cell differentiation.

Proliferation and differentiation of intestinal stem cell (ISC) to replace damaged gut mucosal epithelial cells in inflammatory states is a critical step in ameliorating gut inflammation. However, when this disordered proliferation continues, it induces the ISC to enter a cancerous state. The gut microbiota on the free surface of the gut mucosal barrier is able to interact with ISC on a sustained basis. Microbiota metabolites are able to regulate the proliferation of gut stem and progenitor cells through transcription factors, while in steady state, differentiated colonocytes are able to break down such metabolites, thereby protecting stem cells at the gut crypt. In the future, the gut flora and its metabolites mediating the regulation of ISC differentiation will be a potential treatment for enteropathies.

Does Patellar Denervation with Electrocautery Benefits for Total Knee Arthroplasty without Patellar Resurfacing: A Meta-analysis of Randomized Controlled Trails.

To investigate the effects of patellar denervation (PD) and non-patellar denervation (NPD) after primary total knee arthroplasty (TKA) without patellar resurfacing, this study conducted systematic electronic searches in November 2023 using PubMed, Embase, Web of Science, Cochrane, and Scopus, adhering to Cochrane Collaboration recommendations. Only randomized controlled trials (RCTs) were included. Additionally, a manual search was performed to identify potentially eligible studies from the reference lists of review articles. Two researchers independently conducted literature reviews, data extraction, and risk of bias assessments. The outcome analysis encompassed the incidence of anterior knee pain (AKP), visual analogue scale (VAS), range of motion (ROM), American Knee Society Score (KSS), Oxford Knee Score (OKS), patellar score (PS), complications, and reoperations. Meta-analysis was executed using RevMan 5.3 software. To enhance the credibility of the study, TSA v0.9 software was utilized to perform power analysis on the overall efficacy of primary and secondary outcomes. Twelve studies involving 1745 patients (1587 knees) were included, with 852 undergoing PD and 893 undergoing NPD. Results indicated a superior reduction in AKP incidence in the PD group compared to the NPD group. Statistically significant differences were observed between PD and NPD in KSS, OKS, and PS. However, the upper limit of the 95% confidence interval for each outcome fell below the minimal clinically important difference (MCID). No significant differences were found in VAS and ROM between PD and NPD. Additionally, PD was not associated with an increased incidence of complications or reoperations. Within 12 months and beyond, PD was proven to be a beneficial intervention in reducing AKP following TKA without patellar resurfacing, achieved without an increase in complications or reoperations. Regarding KSS, OKS, and PS, the minimal advantage achievable through PD may not be clinically significant.

Hierarchical global and local auxin signals coordinate cellular interdigitation in Arabidopsis.

The development of multicellular tissues requires both local and global coordination of cell polarization, however, the mechanisms underlying their interplay are poorly understood. In Arabidopsis, leaf epidermal pavement cells (PC) develop a puzzle-piece shape locally coordinated through apoplastic auxin signaling. Here we show auxin also globally coordinates interdigitation by activating the TIR1/AFB-dependent nuclear signaling pathway. This pathway promotes a transient maximum of auxin at the cotyledon tip, which then moves across the leaf activating local PC polarization, as demonstrated by locally uncaged auxin globally rescuing defects in tir1;afb1;afb2;afb4;afb5 mutant but not in tmk1;tmk2;tmk3;tmk4 mutants. Our findings show that hierarchically integrated global and local auxin signaling systems, which respectively depend on TIR1/AFB-dependent gene transcription in the nucleus and TMK-mediated rapid activation of ROP GTPases at the cell surface, control PC interdigitation patterns in Arabidopsis cotyledons, revealing a mechanism for coordinating a local cellular process with the development of whole tissues.

A novel lncRNA LOC101928222 promotes colorectal cancer angiogenesis by stabilizing HMGCS2 mRNA and increasing cholesterol synthesis.

BACKGROUND: Metastasis is the leading cause of mortality in patients with colorectal cancer (CRC) and angiogenesis is a crucial factor in tumor invasion and metastasis. Long noncoding RNAs (lncRNAs) play regulatory functions in various biological processes in tumor cells, however, the roles of lncRNAs in CRC-associated angiogenesis remain to be elucidated in CRC, as do the underlying mechanisms. METHODS: We used bioinformatics to screen differentially expressed lncRNAs from TCGA database. LOC101928222 expression was assessed by qRT-PCR. The impact of LOC101928222 in CRC tumor development was assessed both in vitro and in vivo. The regulatory mechanisms of LOC101928222 in CRC were investigated by cellular fractionation, RNA-sequencing, mass spectrometric, RNA pull-down, RNA immunoprecipitation, RNA stability, and gene-specific m6A assays. RESULTS: LOC101928222 expression was upregulated in CRC and was correlated with a worse outcome. Moreover, LOC101928222 was shown to promote migration, invasion, and angiogenesis in CRC. Mechanistically, LOC101928222 synergized with IGF2BP1 to stabilize HMGCS2 mRNA through an m6A-dependent pathway, leading to increased cholesterol synthesis and, ultimately, the promotion of CRC development. CONCLUSIONS: In summary, these findings demonstrate a novel, LOC101928222-based mechanism involved in the regulation of cholesterol synthesis and the metastatic potential of CRC. The LOC101928222-HMGCS2-cholesterol synthesis pathway may be an effective target for diagnosing and managing CRC metastasis.

Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new click able building blocks remain exceedingly challenging. Here in , we describe a double-click strategy that enables the sequential ligation of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO 2 F) and N-acylsulfamides (RCONHSO 2 NR ´ R ´´ ) in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compound s  exhibit high antimicrobial activities against Gram-positive bacterium  S. aureus and drug-resistant MRSA (MIC up to 6.25·µg mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.

A systematic review and meta-analysis of the effectiveness of social support on turnover intention in clinical nurses.

Background: Nurse turnover has become a salient issue in healthcare system worldwide and seriously compromises patient outcomes. Social support is considered an effective contributor to alleviate nurse turnover intention (TI). However, the degree of correlation between social support and nurse TI remains elusive. Aims: This study aims to evaluate the strength of the effectiveness of social support on TI among nurses as well as its potential moderators. Design: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methods: To obtained qualified studies, two researchers searched Embase, PubMed, Web of science, CINAHL, CNKI, WanFang, and Chinese Medical Journal Full Text Database from inception to January 6, 2024. Meta-analysis, publication bias, and sensitivity analysis were carried out on the included studies using CMA 3.0 software, and the moderating effect was verified through meta-analysis of variance (ANOVA). Results: A total of 38 studies were obtained, involving 63,989 clinical nurses. The comprehensive effect size of the random effect model showed a significant medium negative correlation between social support and TI among nurses (p < 0.001). The sample size and TI measurement tools significantly moderated the correlation between social support and TI (p < 0.050). However, nurse department, gender, data collection time, and social support measurement tools did not moderate the correlation between the two variables. Conclusion: Social support is negatively associated with TI in nurses. Nursing administrators and the medical community should fully recognize the importance of social support for nurses and take corresponding measures to enhance it, thereby reducing TI and ensuring the stability of the nursing team.

Transcriptomic Profiling of Bean Aphid Megoura crassicauda upon Exposure to the Aphid-Obligate Entomopathogen Conidiobolus obscurus (Entomophthoromycotina) and Screening of CytCo-Binding Aphid Proteins through a Pull-Down Assay.

Prolonged periods of host-lethal infection by entomopathogenic fungi pose challenges to the development of biological control agents. The obligate entomopathogen C. obscurus, however, rapidly kills aphid hosts, warranting investigation. This study investigated the interaction between C. obscurus and a bean aphid Megoura crassicauda during the incubation period of infection, using transcriptome analysis to map host gene expression profiles. Results indicate C. obscurus-inoculated aphid activation of the wound healing immune responses, alongside suppression of the key molecules involved in Toll signaling, melanization, and metabolism. Furthermore, neuromotor system-related genes were upregulated, paralleling the intoxication observed in a nematode pest treated with C. obscurus-derived CytCo protein. To deepen interaction insights, a His-tag pull-down assay coupled with mass spectrometry analysis was conducted using CytCo as a bait to screen for potential aphid protein interactors. The proteins were identified based on the assembled transcriptome, and eleven transmembrane proteins were predicted to bind to CytCo. Notably, a protein of putatively calcium-transporting ATPase stood out with the highest confidence. This suggests that CytCo plays a vital role in C. obscurus killing aphid hosts, implicating calcium imbalance. In conclusion, C. obscurus effectively inhibits aphid immunity and exhibits neurotoxic potential, expediting the infection process. This finding facilitates our understanding of the complex host-pathogen interactions and opens new avenues for exploring biological pest management strategies in agroforestry.

Neuroprotective effect of autologous mitochondrial transplantation against global ischemia/reperfusion injury in a rat model of cardiac arrest.

BACKGROUND: Mitochondria have emerged as a promising target for ischemic disease. A previous study reported the application of mitochondrial transplantation in focal cerebral ischemia/reperfusion injury, but it is unclear whether exogenous mitochondrial transplantation could be a therapeutic strategy for global ischemia/reperfusion injury induced by cardiac arrest. METHODS: We hypothesized that transplantation of autologous mitochondria would rescue hippocampal cells and alleviate neurological impairment after cardiac arrest. In this study, we employed a rat cardiac arrest-global cerebral ischemia injury model (CA-GCII) and transplanted isolated mitochondria intravenously. Behavior test was applied to assess neurological deficit. Apoptosis and mitochondria permeability transition pore opening in hippocampus was determined using immunoblotting and swelling assay, respectively. RESULTS: Transplanted mitochondria distributed throughout hippocampal cells and reduced oxidative stress. An improved neurological outcome was observed in rats receiving autologous mitochondria. In the hippocampus, mitophagy was enhanced while cell apoptosis was induced by ischemia/reperfusion insult was downregulated by mitochondrial transplantation. Mitochondrial permeability transition pore (MPTP) opening in surviving hippocampal cells was also suppressed. CONCLUSIONS: These results indicated that transplantation of autologous mitochondria rescued hippocampal cells from ischemia/reperfusion injury and ameliorated neurological impairment caused by cardiac arrest.

Engineering a biomimicking strategy for discovering nonivamide-based quorum-sensing inhibitors for controlling bacterial infection.

The overuse of antibiotics over an extended period has led to increasing antibiotic resistance in pathogenic bacteria, culminating in what is now considered a global health crisis. To tackle the escalating disaster caused by multidrug-resistant pathogens, the development of new bactericides with new action mechanism is highly necessary. In this study, using a biomimicking strategy, a series of new nonivamide derivatives that feature an isopropanolamine moiety [the structurally similar to the diffusible signal factor (DSF) of Xanthomonas spp.] were prepared for serving as potential quorum-sensing inhibitors (QSIs). After screening and investigation of their rationalizing structure-activity relationships (SARs), compound A26 was discovered as the most optimal active molecule, with EC50 values of 9.91 and 7.04 µg mL-1 against Xanthomonas oryzae pv oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). A docking study showed that compound A26 exhibited robust interactions with Glu A: 161 of RpfF, which was strongly evidenced by fluorescence titration assay (KA value for Xoo RpfF-A26 = 104.8709 M-1). Furthermore, various bioassays showed that compound A26 could inhibit various bacterial virulence factors, including biofilm formation, extracellular polysaccharides (EPS), extracellular enzyme activity, DSF production, and swimming motility. In addition, in vivo anti-Xoo results showed that compound A26 had excellent control efficiency (curative activity: 43.55 %; protective activity: 42.56 %), surpassing that of bismerthiazol and thiodiazole copper by approximately 8.0%-37.3 %. Overall, our findings highlight a new paradigm wherein nonivamide derivatives exhibit potential in combating pathogen resistance issues by inhibiting bacterial quorum sensing systems though attributing to their new molecular skeleton, novel mechanisms of action, and non-toxic features.

Effect of apolipoprotein E ε4 and its modification by sociodemographic characteristics on cognitive measures in South Asians from LASI-DAD.

BACKGROUND: We investigated the effects of apolipoprotein E (APOE) ε4 and its interactions with sociodemographic characteristics on cognitive measures in South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD). METHODS: Linear regression was used to assess the association between APOE ε4 and global- and domain-specific cognitive function in 2563 participants (mean age 69.6 ± 7.3 years; 53% female). Effect modification by age, sex, and education were explored using interaction terms and subgroup analyses. RESULTS: APOE ε4 was inversely associated with most cognitive measures (p < 0.05). This association was stronger with advancing age for the Hindi Mental State Examination (HMSE) score (ßε4×age = -0.44, p = 0.03), orientation (ßε4×age = -0.07, p = 0.01), and language/fluency (ßε4×age = -0.07, p = 0.01), as well as in females for memory (ßε4×male = 0.17, p = 0.02) and language/fluency (ßε4×male = 0.12, p = 0.03). DISCUSSION: APOE Îµ4 is associated with lower cognitive function in South Asians from India, with a more pronounced impact observed in females and older individuals. HIGHLIGHTS: APOE Îµ4 carriers had lower global and domain-specific cognitive performance. Females and older individuals may be more susceptible to ε4 effects. For most cognitive measures, there was no interaction between ε4 and education.

Identification of novel 4-substituted 7H-pyrrolo[2,3-d]pyrimidine derivatives as new FtsZ inhibitors: Bioactivity evaluation and computational simulation.

Bacterial infections and the consequent outburst of bactericide-resistance issues are fatal menace to both global health and agricultural produce. Hence, it is crucial to explore candidate bactericides with new mechanisms of action. The filamenting temperature-sensitive mutant Z (FtsZ) protein has been recognized as a new promising and effective target for new bactericide discovery. Hence, using a scaffold-hopping strategy, we designed new 7H-pyrrolo[2,3-d]pyrimidine derivatives, evaluated their antibacterial activities, and investigated their structure-activity relationships. Among them, compound B6 exhibited the optimal in vitro bioactivity (EC50 = 4.65 µg/mL) against Xanthomonas oryzae pv. oryzae (Xoo), which was superior to the references (bismerthiazol [BT], EC50 = 48.67 µg/mL; thiodiazole copper [TC], EC50 = 98.57 µg/mL]. Furthermore, the potency of compound B6 in targeting FtsZ was validated by GTPase activity assay, FtsZ self-assembly observation, fluorescence titration, Fourier-transform infrared spectroscopy (FT-IR) assay, molecular dynamics simulations, and morphological observation. The GTPase activity assay showed that the final IC50 value of compound B6 against XooFtsZ was 235.0 µM. Interestingly, the GTPase activity results indicated that the B6-XooFtsZ complex has an excellent binding constant (KA = 103.24 M-1). Overall, the antibacterial behavior suggests that B6 can interact with XooFtsZ and inhibit its GTPase activity, leading to bacterial cell elongation and even death. In addition, compound B6 showed acceptable anti-Xoo activity in vivo and low toxicity, and also demonstrated a favorable pharmacokinetic profile predicted by ADMET analysis. Our findings provide new chemotypes for the development of FtsZ inhibitors as well as insights into their underlying mechanisms of action.

Precise Molecular Subtyping Reveals Heterogeneity of Lung Adenocarcinoma Based on DNA Methylation.

BACKGROUND: Due to the high heterogeneity of lung adenocarcinoma (LUAD), which restricts the effectiveness of therapy, precise molecular subgrouping of LUAD is of great significance. Clinical research has demonstrated the significant potential of DNA methylation as a classification indicator for human malignancies. METHODS: WGML framework (which was developed based on weighted gene correlation network analysis (WGCNA), Gene Ontology (GO), and machine learning) was developed to precisely subgroup molecular subtypes of LUAD. This framework included two parts: the WG algorithm and the machine learning part. The WG algorithm part was an original algorithm used to obtain a crucial module, which was characterized by weighted correlation network analysis, functional annotation, and mathematical algorithms. The machine learning part utilized the Boruta algorithm, random forest algorithm, and Gradient Boosting Regression Tree algorithm to select feature genes. Then, based on the results of the WGML framework, subtypes were computed by the hierarchical clustering algorithm. A series of analyses, including dimensionality reduction methods, survival analysis, clinical stage analysis, immune infiltration analysis, tumor environment analysis, immune checkpoints analysis, TIDE analysis, CYT analysis, somatic mutation analysis, and drug sensitivity analysis, were utilized to demonstrate the effectiveness of subgrouping. GEO datasets were used to externally validate the results. Meanwhile, another subgrouping method of LUAD from another study was employed to compare with the WGML framework. RESULT: By importing DNA methylation data into the WGML framework, nine genes were obtained to further subgroup LUAD. Three subtypes, the Carcinogenesis subtype, Immune-infiltration subtype, and Chemoresistance subtype, were identified. The dimensionality reduction method exhibited great distinctness between subtypes. A series of analyses were employed to exhibit the difference among the three subtypes and to demonstrate the accuracy of the definition of subtypes. Besides, the WGML framework was compared with a LUAD subgrouping method from another research, which demonstrated that WGML had better efficiency for subgrouping LUAD. CONCLUSION: This study provides a novel LUAD subgrouping framework named WGML for the accurate subgrouping of lung adenocarcinoma.

DPIF-Net: a dual path network for rural road extraction based on the fusion of global and local information.

Background: Automatic extraction of roads from remote sensing images can facilitate many practical applications. However, thus far, thousands of kilometers or more of roads worldwide have not been recorded, especially low-grade roads in rural areas. Moreover, rural roads have different shapes and are influenced by complex environments and other interference factors, which has led to a scarcity of dedicated low level category road datasets. Methods: To address these issues, based on convolutional neural networks (CNNs) and tranformers, this article proposes the Dual Path Information Fusion Network (DPIF-Net). In addition, given the severe lack of low-grade road datasets, we constructed the GaoFen-2 (GF-2) rural road dataset to address this challenge, which spans three regions in China and covers an area of over 2,300 km, almost entirely composed of low-grade roads. To comprehensively test the low-grade road extraction performance and generalization ability of the model, comparative experiments are carried out on the DeepGlobe, and Massachusetts regular road datasets. Results: The results show that DPIF-Net achieves the highest IoU and F1 score on three datasets compared with methods such as U-Net, SegNet, DeepLabv3+, and D-LinkNet, with notable performance on the GF-2 dataset, reaching 0.6104 and 0.7608, respectively. Furthermore, multiple validation experiments demonstrate that DPIF-Net effectively preserves improved connectivity in low-grade road extraction with a modest parameter count of 63.9 MB. The constructed low-grade road dataset and proposed methods will facilitate further research on rural roads, which holds promise for assisting governmental authorities in making informed decisions and strategies to enhance rural road infrastructure.