Synthesis of Novel Propionamide-Methylpyrazole Carboxylates as Herbicidal Candidates.

Transketolase (TKL; EC 2.2.1.1) is a highly promising potential target for herbicidal applications. To identify novel TKL inhibitors, we designed and synthesized a series of 3-oxopropionamide-1-methylpyrazole carboxylate analogues and assessed their herbicidal activities. Ethyl 3-((1-((2,4-dichlorophenyl)amino)-1-oxopropan-2-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylate (D15) and ethyl 1-methyl-3-((1-oxo-1-((thiophen-2-ylmethyl)amino)propan-2-yl)oxy)-1H-pyrazole-5-carboxylate (D20) exhibited superior growth inhibition activities against both the root and stem of Amaranthus retroflexus (A. retroflexus) compared to nicosulfuron and mesotrione. Additionally, D15 achieved an inhibition rate of more than 90% against the roots and stems of Digitaria sanguinalis (D. sanguinalis), outperforming the four control agents at a concentration of 200 mg/L using the small cup method. In the pre-emergence herbicidal activity test, D15 effectively inhibited D. sanguinalis by more than 90% at 150 g ai/ha, surpassing the efficacy of the control, mesotrione. Conversely, in the postemergence herbicidal activity test, D20 exhibited efficient inhibition of A. retroflexus by more than 90% at 150 g ai/ha, outperforming the control agents nicosulfuron, mesotrione, and metamifop. The results of the TKL enzyme activity test showed that the IC50 values of compounds D15 and D20 were 0.384 and 0.655 mg/L, respectively, which were close to those of the control agents. Furthermore, molecular docking and molecular dynamics simulation studies revealed that D15 and D20 interacted favorably with the TKL of Setaria viridis. Such findings highlight the promising potential of D15 and D20 as lead TKL inhibitors for the optimization of new herbicides.

Studies on the Preparation of a Microemulsion Formulation of Matricaria Recutita Essential Oil and the Treatment of 2,4-Dinitro-Chlorobenzene- Induced Eczema in Mice by Inhibiting Inflammation.

BACKGROUND: Eczema, an inflammatory skin disease causing intense itching, is a function of a range of internal and external factors, impacting individuals of all ages and leading to economic loss. Inflammation is the most important manifestation of eczema, and Matricaria recutita essential oil (MREO) extracted from Matricaria recutita possesses excellent antibacterial and anti-inflammatory properties. METHODS: In this study, Matricaria recutita microemulsions were prepared by the trans-phase emulsification method and their stability was determined by evaluating the relevant indexes. Establishment of 2,4-dinitro-chlorobenzene-induced AD model in mice. Detection of serum indexes of IL-6, IL-17, and TNF-α, and on pathological tissue sections, the HE staining, toluidine blue staining, immunohistochemistry, and observation were performed. RESULTS: The study obtained optimal conditions for the preparation of microemulsion formulations of Matricaria recutita. Through quality evaluation, it was found that the microemulsion increased stability, reduced irritation, and retained anti-inflammatory activity and therapeutic effects on eczema compared to Matricaria recutita essential oil (MREO). Studies have demonstrated that microemulsion formulations of Matricaria recutita and Matricaria recutita significantly down regulate the proinflammatory factors TNF-α, IL-17, and IL-6. It was shown by hematoxylin-eosin (HE) staining that both Matricaria recutita essential oil (MREO) and Matricaria recutita microemulsion (MRME) improved the inflammatory status of eczematous skin tissues in mice. The number of mast cells expressed in the tissues was decreased in the surface-treated group, as shown by toluidine blue staining. Additionally, the number of mast cells expressed in the tissues in the surface-treated group was reduced, as demonstrated by immunohistochemistry. Furthermore, immunohistochemistry revealed that MREO and MRME have immunomodulatory effects on the tissues. CONCLUSION: The study showed that microemulsion formulations of Matricaria recutita may serve as a novel remedy for eczema.

The protective effects of aqueous extract of Schisandra sphenanthera against alcoholic liver disease partly through the PI3K-AKT-IKK signaling pathway.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P < 0.05); Western blotting and immunohistochemical analyses showed that the expression levels of phosphorylated PI3K, AKT, IKK, NFκB, and FOXO1 proteins were significantly reduced in liver tissues (P < 0.05), whereas the expression level of Bcl-2 proteins was significantly increased (P < 0.05). Conclusion: The active components of SSAE were schisandrin A, schisandrol A, and schisandrol B, which regulated the phosphorylation levels of PI3K, AKT, IKK, and NFκB and the expression of FOXO1 protein and upregulated the expression of Bcl-2 protein in the liver tissues of ALD rats. These findings indicate that SSAE acts against ALD partly through the PI3K-AKT-IKK signaling pathway. This study provided a reference for future research and treatment of ALD and the development of novel natural hepatoprotective drugs.

Integrating pathogen- and host-derived blood biomarkers for enhanced tuberculosis diagnosis: a comprehensive review.

This review explores the evolving landscape of blood biomarkers in the diagnosis of tuberculosis (TB), focusing on biomarkers derived both from the pathogen and the host. These biomarkers provide critical insights that can improve diagnostic accuracy and timeliness, essential for effective TB management. The document highlights recent advancements in molecular techniques that have enhanced the detection and characterization of specific biomarkers. It also discusses the integration of these biomarkers into clinical practice, emphasizing their potential to revolutionize TB diagnostics by enabling more precise detection and monitoring of the disease progression. Challenges such as variability in biomarker expression and the need for standardized validation processes are addressed to ensure reliability across different populations and settings. The review calls for further research to refine these biomarkers and fully harness their potential in the fight against TB, suggesting a multidisciplinary approach to overcome existing barriers and optimize diagnostic strategies. This comprehensive analysis underscores the significance of blood biomarkers as invaluable tools in the global effort to control and eliminate TB.

Breathomics for diagnosing tuberculosis in diabetes mellitus patients.

Introduction: Individuals with diabetes mellitus (DM) are at an increased risk of Mycobacterium tuberculosis (Mtb) infection and progressing from latent tuberculosis (TB) infection to active tuberculosis disease. TB in the DM population is more likely to go undiagnosed due to smear-negative results. Methods: Exhaled breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry. An eXtreme Gradient Boosting (XGBoost) model was utilized for breathomics analysis and TB detection. Results: XGBoost model achieved a sensitivity of 88.5%, specificity of 100%, accuracy of 90.2%, and an area under the curve (AUC) of 98.8%. The most significant feature across the entire set was m106, which demonstrated a sensitivity of 93%, specificity of 100%, and an AUC of 99.7%. Discussion: The breathomics-based TB detection method utilizing m106 exhibited high sensitivity and specificity potentially beneficial for clinical TB screening and diagnosis in individuals with diabetes.

Variations in Quinolinic Acid Levels in Tuberculosis Patients with Diabetes Comorbidity: A Pilot Prospective Cohort Study.

Objective: We aimed to investigate dysregulated metabolic pathways and identify diagnostic and therapeutic targets in patients with tuberculosis-diabetes (TB-DM). Methods: In our prospective cohort study, plasma samples were collected from healthy individuals, diabetic (DM) patients, untreated TB-only (TB-0)/TB-DM patients (TB-DM-0), and cured TB (TB-6)/TB-DM patients (TB-DM-6) to measure the levels of amino acids, fatty acids, and other metabolites in plasma using high-throughput targeted quantification methods. Results: Significantly different biological processes and biomarkers were identified in DM, TB-DM-0, and TB-DM-6 patients. Moreover, quinolinic acid (QA) showed excellent predictive accuracy for distinguishing between DM patients and TB-DM-0 patients, with an AUC of 1 (95% CI 1-1). When differentiating between TB-DM-0 patients and TB-DM-6 patients, the AUC was 0.9297 (95% CI 0.8460-1). Compared to those in DM patients, the QA levels were significantly elevated in TB-DM-0 patients and decreased significantly after antituberculosis treatment. We simultaneously compared healthy controls and untreated tuberculosis patients and detected an increase in the level of QA in the plasma of tuberculosis patients, which decreased following treatment. Conclusion: These findings improve the current understanding of tuberculosis treatment in patients with diabetes. QA may serve as an ideal diagnostic biomarker for TB-DM patients and contribute to the development of more effective treatments.

Data-Driven and Machine Learning to Screen Metal-Organic Frameworks for the Efficient Separation of Methane.

With the rapid growth of the economy, people are increasingly reliant on energy sources. However, in recent years, the energy crisis has gradually intensified. As a clean energy source, methane has garnered widespread attention for its development and utilization. This study employed both large-scale computational screening and machine learning to investigate the adsorption and diffusion properties of thousands of metal-organic frameworks (MOFs) in six gas binary mixtures of CH4 (H2/CH4, N2/CH4, O2/CH4, CO2/CH4, H2S/CH4, He/CH4) for methane purification. Firstly, a univariate analysis was conducted to discuss the relationships between the performance indicators of adsorbents and their characteristic descriptors. Subsequently, four machine learning methods were utilized to predict the diffusivity/selectivity of gas, with the light gradient boosting machine (LGBM) algorithm emerging as the optimal one, yielding R2 values of 0.954 for the diffusivity and 0.931 for the selectivity. Furthermore, the LGBM algorithm was combined with the SHapley Additive exPlanation (SHAP) technique to quantitatively analyze the relative importance of each MOF descriptor, revealing that the pore limiting diameter (PLD) was the most critical structural descriptor affecting molecular diffusivity. Finally, for each system of CH4 mixture, three high-performance MOFs were identified, and the commonalities among high-performance MOFs were analyzed, leading to the proposals of three design principles involving changes only to the metal centers, organic linkers, or topological structures. Thus, this work reveals microscopic insights into the separation mechanisms of CH4 from different binary mixtures in MOFs.

Reversible ON- and OFF-switch receptors Clec4G and Rab1A reveal the hormetic effects of a pectin polysaccharide in Aralia elata (Miq.) Seem.

BACKGROUND: Numerous studies indicate that natural polysaccharides have immune-enhancing effects as a host defense potentiator. Few reports are available on hormetic effects of natural polysaccharides, and the underlying mechanisms remain unclear. PURPOSE: AELP-B6 (arabinose- and galactose-rich pectin polysaccharide) from Aralia elata (Miq.) Seem was taken as a case study to clarify the potential mechanism of hormetic effects of natural polysaccharides. METHODS: The pharmacodynamic effect of AELP-B6 was verified by constructing the CTX-immunosuppressive mouse model. The hormetic effects were explored by TMT-labeled proteomics, energy metabolism analysis, flow cytometry and western blot. The core-affinity target of AELP-B6 was determined by pull down, nanoLC-nanoESI+-MS, CETSA, immunoblot and SPR assay. The RAW264.7Clec4G-RFP and RAW264.7Rab1A-RFP cell lines were simultaneously constructed to determine the affinity difference between AELP-B6 and targets by confocal laser scanning live-cell imaging. Antibody blocking assays were further used to verify the mechanism of hormetic effects. RESULTS: AELP-B6 at low and medium doses may maintain the structural integrity of thymus and spleen, increase the concentrations of TNF-α, IFN-γ, IL-3 and IL-8, and alleviate CTX-induced reduction of immune cell viability in vivo. Proteomics and energy metabolism analysis revealed that AELP-B6 regulate HIF-1α-mediated metabolic programming, causing Warburg effects in macrophages. AELP-B6 at low and medium doses promoted the release of intracellular immune factors, and driving M1-like polarization of macrophages. As a contrast, AELP-B6 at high dose enhanced the expression levels of apoptosis related proteins, indicating activation of the intrinsic apoptotic cascade. Two highly expressed transmembrane proteins in macrophages, Clec4G and Rab1A, were identified as the primary binding targets of AELP-B6 which co-localized with the cell membrane and directly impacted with immune cell activation and apoptosis. AELP-B6 exhibits affinity differences with Clec4G and Rab1A, which is the key to the hormetic effects. CONCLUSION: We observed hormesis of natural polysaccharide (AELP-B6) for the first time, and AELP-B6 mediates the hormetic effects through two dose-related targets. Low dose of AELP-B6 targets Clec4G, thereby driving the M1-like polarization via regulating NF-κB signaling pathway and HIF-1α-mediated metabolic programming, whereas high dose of AELP-B6 targets Rab1A, leading to mitochondria-dependent apoptosis.

Myriocin enhances the clearance of M. tuberculosis by macrophages through the activation of PLIN2.

Myriocin is an inhibitor of de novo synthesis of sphingolipids and ceramides. In this research, we showed myriocin could significantly reduce Mtb burden and histopathological inflammation in mice. However, the underlying mechanism remains unclear. RNA-seq analysis revealed a significant increase in gene expression of PLIN2/CD36/CERT1 after myriocin treatment. The reduced bactericidal burden was only reversed after silencing the lipid droplets (LDs) surface protein PLIN2. This suggests that myriocin enhances the ability of macrophages to clear Mtb depending on the PLIN2 gene, which is part of the PPARγ pathway. Indeed, we observed a significant increase in the number of LDs following myriocin treatment.IMPORTANCEMycobacterium tuberculosis has the ability to reprogram host cell lipid metabolism and alter the antimicrobial functions of infected macrophages. The sphingolipids, such as ceramides, are the primary host lipids utilized by the bacteria, making the sphingomyelinase/ceramide system critical in Mtb infections. Surprisingly, the antimicrobial effect of myriocin was found to be independent of its role in reducing ceramides, but instead, it depends on the lipid droplets surface protein PLIN2. Our findings provide a novel mechanism for how myriocin enhances Mtb clearance in macrophages.

Discovery of novel Propionamide-Pyrazole-Carboxylates as Transketolase-inhibiting herbicidal candidates.

BACKGROUND: Transketolase (TKL, EC 2.2.1.1) is a key enzyme in the pentose phosphate pathway and Calvin cycle, and is expected to act as a herbicidal site-of-action. On the basis of TKL, we designed and synthesized a series of 1-oxy-propionamide-pyrazole-3-carboxylate analogues and evaluated their herbicidal activities. RESULTS: Methyl 1-methyl-5-((1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C23) and methyl 1-methyl-5-((1-oxo-1-((perfluorophenyl)amino)propan-2-yl)oxy)-1H-pyrazole-3-carboxylate (C33) were found to provide better growth-inhibition activities against Digitaria sanguinalis root than those of nicosulfuron, mesotrione and pretilachlor at 200 mg L-1 using the small-cup method. These compounds were also identified as promising compounds in pre-emergence and postemergence herbicidal-activity experiments, with relatively good inhibitory effects toward Amaranthus retroflexus and D. sanguinalis at 150 g ai ha-1. In addition, enzyme inhibition assays and molecular docking studies revealed that C23 and C33 interact favourably with SvTKL (Setaria viridis TKL). CONCLUSION: C23 and C33 are promising lead TKL inhibitors for the optimization of new herbicides. © 2024 Society of Chemical Industry.

High-Molecular-Weight Hyaluronic Acid Can Be Used as a Food Additive to Improve the Symptoms of Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS).

Hyaluronic acid (HA) is a new functional food additive which has the potential to ameliorate persistent inflammation, immunosuppression and catabolism syndrome (PICS), but the biological effects of HA with various molecular weights differ dramatically. To systematically investigate the efficacy of HA in altering PICS symptoms, medium-molecular-weight (MMW) HA was specifically selected to test its intervention effect on a PICS mouse model induced by CLP through oral administration, with high-molecular-weight (HMW) and low-molecular-weight (LMW) HA also participating in the experimental validation process. The results of pathological observations and gut flora showed that MMW HA rapidly alleviated lung lesions and intestinal structural changes in PICS mice in the short term. However, although long-term MMW HA administration significantly reduced the proportions of harmful bacteria in gut flora, inflammatory responses in the intestines and lungs of PICS mice were significantly higher in the MMW HA group than in the HMW HA and LMW HA groups. The use of HMW HA not only rapidly reduced the mortality rate of PICS mice but also improved their grip strength and the recovery of spleen and thymus indices. Furthermore, it consistently promoted the recovery of lung and intestinal tissues in PICS mice, and it also assisted in the sustained restoration of their gut microbiota. These effects were superior to those of LMW HA and MMW HA. The experimental results indicate that HMW weight HA has the greatest potential to be an adjunct in alleviating PICS as a food additive, while the safety of other HAs requires further attention.

Preparation of pH-sensitive carboxymethyl chitosan nanoparticles loaded with ginsenoside Rb1 and evaluation of drug release in vitro.

Oral absorption of ginsenoside Rb1 (Rb1) is often hindered by the gastrointestinal tract. Carboxymethyl chitosan deoxycholic acid loaded with ginsenoside Rb1 nanoparticles (CMDA@Rb1-NPs), were prepared as a delivery system using a self-assembly technique with amphipathic deoxycholic acid grafted carboxymethyl chitosan as the carrier, which improved the stability and embedding rate of Rb1. In addition, the CMDA@Rb1-NPs was encapsulated with sodium alginate by ion crosslinking method with additional layer (CMDAlg@Rb1-NPs). Scanning electron microscopy showed that the nanoparticles were spherical, evenly distributed, smooth and without obvious adhesion. By evaluating drug loading, entrapment efficiency, the encapsulation efficiency of Rb1 increased from 60.07 % to 72.14 % after grafting deoxycholic acid improvement and optimization. In vitro release results showed that the cumulative release of Rb1 by CMDAlg-NPs showed a pH dependent effect, which was <10 % in simulated gastric juice with pH 1.2, completely released with pH 7.4 for about 48 h. In addition, Rb1 and CMDAlg@Rb1-NPs had inhibitory effects on A549 cells, and the inhibitory effect of CMDAlg@Rb1-NPs was better. Therefore, all results indicated that CMDA/Alg@Rb1 nanoparticles might be a novel drug delivery system to improve the stability and embedding rate of Rb1, and has the potential to be applied in oral pharmaceutical preparations.

Dihydrotanshinone I inhibits gallbladder cancer growth by targeting the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation.

BACKGROUND: Gallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from Salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear. PURPOSE: To explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms. METHODS: The proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice. RESULTS: Our research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells. CONCLUSION: Our findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment.

Clinical application of indocyanine green fluorescence navigation technique in laparoscopic common bile duct exploration for complex hepatolithiasis.

BACKGROUND: This study investigated the clinical application of the indocyanine green (ICG) fluorescence navigation technique in bile duct identification during laparoscopic common bile duct exploration (LCBDE) for complex hepatolithiasis. METHODS: Eighty patients with complex hepatolithiasis were admitted to our department between January 2022 and June 2023 and randomly divided into control and observation groups. The control group underwent conventional LCBDE, while the observation group underwent LCBDE guided by ICG fluorescence. RESULTS: Intraoperatively, the observation group had shorter operation and search times for the common bile duct (CBD), as well as reduced intraoperative blood loss and fewer complications, such as conversion to laparotomy and various injuries (gastroduodenal, colon, pancreatic, and vascular) than the control group, with statistical significance (P < 0.05). Postoperatively, the observation group had lower rates of postoperative bile leakage, abdominal infection, postoperative hemorrhage, and residual stone than the control group. Additionally, the observation group demonstrated significantly shorter times for resuming flatus, removal of the abdominal drainage tube, and hospitalization than the control group, with statistical significance (P < 0.05). CONCLUSION: ICG fluorescence navigation technology effectively visualizes the bile duct, improves its identification rate, shortens the operation time, prevents biliary tract injury, and reduces the occurrence of complications.

Real-World Effectiveness of Ustekinumab in Ulcerative Colitis in a United States Multicenter Cohort Consortium.

BACKGROUND: Pivotal trials have shown that ustekinumab is effective in ulcerative colitis (UC). However, the population included in these trials do not represent the cohort of patients treated in the real world. In this study, we aimed to describe the effectiveness and safety of ustekinumab in a clinical cohort of patients with UC. METHODS: We performed a multicenter retrospective cohort study and included patients with active UC starting ustekinumab. Variables collected included demographics, clinical data, and disease activity (measured using partial Mayo score [PMS] and endoscopic Mayo score) at follow-up. The primary outcomes were cumulative rates of steroid-free clinical and biochemical remission (SFCBR), defined as a PMS <2 while off steroids and a normal C-reactive protein and/or fecal calprotectin. RESULTS: A total of 245 patients met inclusion criteria. The median time of follow-up was 33 (interquartile range, 17-53) weeks, and 214 (87.3%) had previous exposure to a biologic and/or tofacitinib. Rates of SFCBR, clinical remission, and endoscopic remission at 6 and 12 months were 12.0% (n = 16 of 139), 29.0% (n = 71 of 175), and 18.0% (n = 7 of 39), and 23.8% (n = 15 of 63), 54.3% (n = 57 of 105), and 31.0% (n = 9 of 29), respectively. Non-Hispanic White race, higher baseline PMS, and the use of concomitant corticosteroids were independently associated with failure to achieve SFCBR. Of the 73 that were dose escalated, 28.4% did not respond, 49.3% experienced a benefit, and 21.6% achieved remission. CONCLUSIONS: In a population enriched with refractory UC, ustekinumab was well tolerated and induced remission in a significant number of patients. Larger studies with a longer follow-up are warranted.

Ustekinumab was shown to be efficacious and safe in a population of patients with refractory ulcerative colitis. Those patients with exposure to multiple drug classes and higher disease burden at baseline are less likely to respond.

LncRNA PCAT6 is a predictor of poor prognosis of colorectal cancer.

Background: The long non-coding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) has been studied in many cancers, yet its relationship with colorectal cancer (CRC) remains poorly defined. Here, we conducted an analysis of The Cancer Genome Atlas (TCGA) database to better clarify the role of PCAT6 in this cancer type. Methods: Wilcoxon rank-sum tests were utilized to assess relative levels of PCAT6 in CRC tumors and normal tissues, while logistic regression analyses were utilized to compare the relationships between PCAT6 levels and clinicopathological findings. Kaplan-Meier curves and Cox regression analyses were used to gauge correlations between PCAT6 and patient survival outcomes, while the biological roles of this lncRNA were investigated via a gene set enrichment analysis (GSEA) approach. The expression level of PCAT6 in CRC cell lines was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: PCAT6 levels were significantly correlated with CRC patient lymph node metastasis (N) stage [odds ratio (OR) =1.8 for N1 & N2 vs. N0], lymphatic invasion [OR =1.9 for yes vs. no), distant metastasis (M stage) (OR =2.1 for M1 vs. M0), carcinoembryonic antigen (CEA) level (OR =1.9 for >5 vs. ≤5), perineural invasion (OR =1.9 for yes vs. no), pathologic stage (OR =1.9 for stage III/IV vs. stage I/II), and neoplasm type (OR =2.1 for rectal adenocarcinoma vs. colon adenocarcinoma) (all P<0.05). CRC patients expressing higher PCAT6 levels exhibited poorer survival outcomes than those expressing low levels of this lncRNA (P=0.017), and in univariate analyses, higher PCAT6 levels were linked to worse overall survival [hazard ratio (HR) =1.540; 95% confidence interval (CI): 1.079-2.199; P=0.017], with this relationship also being preserved in a multivariate analysis (HR =6.892; 95% CI: 1.713-27.727, P=0.007). GSEA revealed high PCAT6 expression to be linked to differential DNA methylation enrichment, with high PCAT6 levels being associated with changes in base excision repair, cellular senescence, G2/M DNA damage checkpoint, chromatin-modifying enzyme, and gene silencing by RNA activity. The high expression of lncRNA PCAT6 in CRC cell lines was demonstrated by PCR experiments. Conclusions: PCAT6 represents a promising prognostic biomarker of poor CRC patient survival outcomes, with DNA methylation and RNA-mediated gene silencing being potentially promising mechanistic pathways whereby this lncRNA may shape patient outcomes.

Discovery of Novel Pyrazole Acyl Thiourea Skeleton Analogue as Potential Herbicide Candidates.

To discover novel transketolase (TKL, EC 2.2.1.1) inhibitors with potential herbicidal applications, a series of pyrazole acyl thiourea derivatives were designed based on a previously obtained pyrazolamide acyl lead compound, employing a scaffold hopping strategy. The compounds were synthesized, their structures were characterized, and they were evaluated for herbicidal activities. The results indicate that 7a exhibited exceptional herbicidal activity against Digitaria sanguinalis and Amaranthus retroflexus at a dosage of 90 g ai/ha, using the foliar spray method in a greenhouse. This performance is comparable to that of commercial products, such as nicosulfuron and mesotrione. Moreover, 7a showed moderate growth inhibitory activity against the young root and stem of A. retroflexus at 200 mg/L in the small cup method, similar to that of nicosulfuron and mesotrione. Subsequent mode-of-action verification experiments revealed that 7a and 7e inhibited Setaria viridis TKL (SvTKL) enzyme activity, with IC50 values of 0.740 and 0.474 mg/L, respectively. Furthermore, they exhibited inhibitory effects on the Brassica napus acetohydroxyacid synthase enzyme activity. Molecular docking predicted potential interactions between these (7a and 7e) and SvTKL. A greenhouse experiment demonstrated that 7a exhibited favorable crop safety at 150 g ai/ha. Therefore, 7a is a promising herbicidal candidate that is worthy of further development.

Efficient Direct X-ray Detection and Imaging Based on a Lead-Free Electron Donor-Acceptor MOF.

Metal-organic frameworks (MOFs) have recently gained extensive attention as potential materials for direct radiation detection due to their strong radiation absorption, long-range order, and chemical tunability. However, it remains challenging to develop a practical MOF-based X-ray direct detector that possesses high X-ray detection efficiency, radiation stability, and environmental friendliness. The integration of donor-acceptor (D-A) pairs into crystalline MOFs is a powerful strategy for the precise fabrication of multifunctional materials with unique optoelectronic properties. Herein, a new lead-free MOF, Cu2I2(TPPA) (CuI-TPPA, TPPA = tris[4-(pyridine-4-yl)phenyl]amine), with a 6-fold interpenetrated structure is designed and synthesized based on the electron donor-acceptor strategy. CuI-TPPA has a large mobility-lifetime (µτ) product of 5.8 × 10-4 cm2 V-1 and a high detection sensitivity of 73.1 µC Gyair-1 cm-2, surpassing that of commercial α-Se detectors. Moreover, the detector remains fairly stable with only a 2% reduction in photocurrent under continuous bias irradiation conditions with a total dose of over 42.83 Gyair. The CuI-TPPA/poly(vinylidene fluoride) flexible composite X-ray detector films are successfully manufactured with different thicknesses. Through multifaceted assessments, the optimal thickness is found with a high detection sensitivity of up to 143.6 µC Gyair-1 cm-2. As proof-of-concept, 11 × 9 pixelated X-ray detectors are fabricated on the same composite film to realize X-ray direct imaging. This work opens up potential applications of MOFs in environmentally friendly and wearable devices for direct X-ray detection and imaging.