"Hepatic hilum area priority, liver posterior first": An optimized strategy in laparoscopic resection for type III-IV hilar cholangiocarcinoma.

BACKGROUND: In recent years, pure laparoscopic radical surgery for Bismuth-Corlette type III and IV hilar cholangiocarcinoma (HCCA) has been preliminarily explored and applied, but the surgical strategy and safety are still worthy of further improvement and attention. AIM: To summarize and share the application experience of the emerging strategy of "hepatic hilum area dissection priority, liver posterior separation first" in pure laparoscopic radical resection for patients with HCCA of Bismuth-Corlette types III and IV. METHODS: The clinical data and surgical videos of 6 patients with HCCA of Bismuth-Corlette types III and IV who underwent pure laparoscopic radical resection in our department from December 2021 to December 2023 were retrospectively analyzed. RESULTS: Among the 6 patients, 4 were males and 2 were females. The average age was 62.2 ± 11.0 years, and the median body mass index was 20.7 (19.2-24.1) kg/m2. The preoperative median total bilirubin was 57.7 (16.0-155.7) µmol/L. One patient had Bismuth-Corlette type IIIa, 4 patients had Bismuth-Corlette type IIIb, and 1 patient had Bismuth-Corlette type IV. All patients successfully underwent pure laparoscopic radical resection following the strategy of "hepatic hilum area dissection priority, liver posterior separation first". The operation time was 358.3 ± 85.0 minutes, and the intraoperative blood loss volume was 195.0 ± 108.4 mL. None of the patients received blood transfusions during the perioperative period. The median length of stay was 8.3 (7.0-10.0) days. Mild bile leakage occurred in 2 patients, and all patients were discharged without serious surgery-related complications. CONCLUSION: The emerging strategy of "hepatic hilum area dissection priority, liver posterior separation first" is safe and feasible in pure laparoscopic radical surgery for patients with HCCA of Bismuth-Corlette types III and IV. This strategy is helpful for promoting the modularization and process of pure laparoscopic radical surgery for complicated HCCA, shortens the learning curve, and is worthy of further clinical application.

Metalenses phase characterization by multi-distance phase retrieval.

Metalens, characterized by their unique functions and distinctive physical properties, have gained significant attention for their potential applications. To further optimize the performance of metalens, it is necessary to characterize the phase modulation of the metalens. In this study, we present a multi-distance phase retrieval system based on optical field scanning and discuss its convergence and robustness. Our findings indicate that the system is capable of retrieving the phase distribution of the metalens as long as the measurement noise is low and the total length of the scanned light field is sufficiently long. This system enables the analysis of focal length and aberration by utilizing the computed phase distribution. We extend our investigation to measure the phase distribution of the metalens operating in the near-infrared (NIR) spectrum and identify the impact of defects in the sample on the phase. Additionally, we conduct a comparative analysis of the phase distribution of the metalens in air and ethanol and observe the variations in the phase modulation of the metalens in different working mediums. Our system provides a straightforward method for the phase characterization of metalens, aiding in optimizing the metalens design and functionality.

Identification and analysis of key genes related to efferocytosis in colorectal cancer.

The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND: It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS: In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION: Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.

Pharmacological inhibition of Septins with Forchlorfenuron attenuates thrombus formation in experimental thrombotic mice models with modulating multiple signaling pathways in platelets.

INTRODUCTION: The Septin family of cytoskeletal proteins is abundant in platelets. When these proteins are functionally blocked using the compound forchlorfenuron (FCF), it hampers the normal activation processes of purified human platelets. OBJECTIVES: To evaluate the in vivo effects of FCF on physiological haemostasis and pathological thrombosis in mice and to investigate possible molecular mechanisms. METHODS: The impact of FCF on haemorrhage risk in the brain, liver, and tail of mice was investigated. Using several experimental models, thrombus development in the lung, mesenteric arteries, and postcava was studied. Functional assays were performed on mice and human platelets, both with and without FCF pretreatment. These tests included aggregation, granule release, ROS production, integrin αIIbß3 activation, cytoskeletal remodeling imaging, and clot retraction. RESULTS: Neither oral nor intravenous administration of FCF showed any apparent impairment of haemostasis in the tissues studied, but only later administration resulted in a significant reduction in thrombus formation in different mice vessel types. FCF generally inhibited agonist-induced platelet aggregation, degranulation, ROS burst, morphological expansion on the fibrinogen matrix with completely disordered dynamic organizations of the cytoskeleton for septin, tubulin and actin. In addition, FCF was found to antagonise agonist-induced dephosphorylation of VASP (Ser239) and PI3K/AKT and ERK1/2 phosphorylation. CONCLUSION: FCF showed preferences in attenuating pathological thrombus formation, apart from physiological haemostasis, with possible mechanisms to prevent cytoskeletal remodelling and signal transduction of AKT, ERK1/2 and VASP signalling pathways, suggesting that Septin may serve as a promising target for the prevention and treatment of thrombotic diseases.

A Small "Tent" in the Esophagus.

Cite this article as: Zong Z, Xu J, Zhang H, Xu H, Tang X, Shi L. A small "tent" in the esophagus. Turk J Gastroenterol. 2024;35(7): 587-588.

Chloroplast and whole-genome sequencing shed light on the evolutionary history and phenotypic diversification of peanuts.

Cultivated peanut (Arachis hypogaea L.) is a widely grown oilseed crop worldwide; however, the events leading to its origin and diversification are not fully understood. Here by combining chloroplast and whole-genome sequence data from a large germplasm collection, we show that the two subspecies of A. hypogaea (hypogaea and fastigiata) likely arose from distinct allopolyploidization and domestication events. Peanut genetic clusters were then differentiated in relation to dissemination routes and breeding efforts. A combination of linkage mapping and genome-wide association studies allowed us to characterize genes and genomic regions related to main peanut morpho-agronomic traits, namely flowering pattern, inner tegument color, growth habit, pod/seed weight and oil content. Together, our findings shed light on the evolutionary history and phenotypic diversification of peanuts and might be of broad interest to plant breeders.

Dehydrogenative cyclization of 2-arylbenzoic acid and 2-arylbenzamide with hydrogen evolution in a photoelectrochemical cell.

This paper describes photoelectrochemical dehydrogenative cyclization of 2-arylbenzoic acid and 2-arylbenzamide in a PEC cell consisting of a mesoporous WO3 photoanode and Pt cathode. The cyclization reaction is effectively driven by this PEC system at room temperature with blue LED irradiation under external oxidant- and metal-free conditions, delivering a series of benzolactones and benzolactams in up to 95% isolated yields. Meanwhile, hydrogen is released as the only byproduct of this process.

Deep learning-aided respiratory motion compensation in PET/CT: addressing motion induced resolution loss, attenuation correction artifacts and PET-CT misalignment.

PURPOSE: Respiratory motion (RM) significantly impacts image quality in thoracoabdominal PET/CT imaging. This study introduces a unified data-driven respiratory motion correction (uRMC) method, utilizing deep learning neural networks, to solve all the major issues caused by RM, i.e., PET resolution loss, attenuation correction artifacts, and PET-CT misalignment. METHODS: In a retrospective study, 737 patients underwent [18F]FDG PET/CT scans using the uMI Panorama PET/CT scanner. Ninety-nine patients, who also had respiration monitoring device (VSM), formed the validation set. The remaining data of the 638 patients were used to train neural networks used in the uRMC. The uRMC primarily consists of three key components: (1) data-driven respiratory signal extraction, (2) attenuation map generation, and (3) PET-CT alignment. SUV metrics were calculated within 906 lesions for three approaches, i.e., data-driven uRMC (proposed), VSM-based uRMC, and OSEM without motion correction (NMC). RM magnitude of major organs were estimated. RESULTS: uRMC enhanced diagnostic capabilities by revealing previously undetected lesions, sharpening lesion contours, increasing SUV values, and improving PET-CT alignment. Compared to NMC, uRMC showed increases of 10% and 17% in SUVmax and SUVmean across 906 lesions. Sub-group analysis showed significant SUV increases in small and medium-sized lesions with uRMC. Minor differences were found between VSM-based and data-driven uRMC methods, with the SUVmax was found statistically marginal significant or insignificant between the two methods. The study observed varied motion amplitudes in major organs, typically ranging from 10 to 20 mm. CONCLUSION: A data-driven solution for respiratory motion in PET/CT has been developed, validated and evaluated. To the best of our knowledge, this is the first unified solution that compensates for the motion blur within PET, the attenuation mismatch artifacts caused by PET-CT misalignment, and the misalignment between PET and CT.

Circadian Rhythm and Nitrogen Metabolism Participate in the Response of Boron Deficiency in the Root of Brassica napus.

Boron (B) deficiency has been shown to inhibit root cell growth and division. However, the precise mechanism underlying B deficiency-mediated root tip growth inhibition remains unclear. In this study, we investigated the role of BnaA3.NIP5;1, a gene encoding a boric acid channel, in Brassica napus (B. napus). BnaA3.NIP5;1 is expressed in the lateral root cap and contributes to B acquisition in the root tip. Downregulation of BnaA3.NIP5;1 enhances B sensitivity in B. napus, resulting in reduced shoot biomass and impaired root tip development. Transcriptome analysis was conducted on root tips from wild-type B. napus (QY10) and BnaA3.NIP5;1 RNAi lines to assess the significance of B dynamics in meristematic cells during seedling growth. Differentially expressed genes (DEGs) were significantly enriched in plant circadian rhythm and nitrogen (N) metabolism pathways. Notably, the circadian-rhythm-related gene HY5 exhibited a similar B regulation pattern in Arabidopsis to that observed in B. napus. Furthermore, Arabidopsis mutants with disrupted circadian rhythm (hy5/cor27/toc1) displayed heightened sensitivity to low B compared to the wild type (Col-0). Consistent with expectations, B deficiency significantly disrupted N metabolism in B. napus roots, affecting nitrogen concentration, nitrate reductase enzyme activity, and glutamine synthesis. Interestingly, this disruption was exacerbated in BnaA3NIP5;1 RNAi lines. Overall, our findings highlight the critical role of B dynamics in root tip cells, impacting circadian rhythm and N metabolism, ultimately leading to retarded growth. This study provides novel insights into B regulation in root tip development and overall root growth in B. napus.

Prognostic Impact of Neoadjuvant Chemotherapy in Localized or Locoregionally Advanced Gallbladder Cancer: A Population-Based and Propensity Score Matched SEER Analysis.

BACKGROUND: The effect of neoadjuvant chemotherapy (NACT) in gallbladder cancer (GBC) patients remains controversial. The aim of this study was to assess the impact of NACT on overall survival (OS) and cancer specific survival (CSS) in patients with localized or locoregionally advanced GBC, and to explore possible protective predictors for prognosis. METHODS: Data for patients with localized or locoregionally advanced GBC (i.e., categories cTx-cT4, cN0-2, and cM0) from 2004 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients in the NACT and non-NACT groups were propensity score matched (PSM) 1:3, and the Kaplan-Meier method and log-rank test were performed to analyze the impact of NACT on OS and CSS. Univariable and multivariable Cox regression models were applied to identify the possible prognostic factors. Subgroup analysis was conducted to identify patients who would benefit from NACT. RESULTS: Of the 2676 cases included, 78 NACT and 234 non-NACT patients remained after PSM. In localized or locoregionally advanced GBC patients, the median OS of the NACT and non-NACT was 31 and 16 months (log-rank P < 0.01), and the median CSS of NACT and non-NACT was 32 and 17 months (log-rank P < 0.01), respectively. Longer median OS (31 vs 17 months, log-rank P < 0.01) and CSS (32 vs 20 months, log-rank P < 0.01) was associated with NACT compared with surgery alone. Multivariable Cox regression analysis showed that NACT, stage, and surgery type were prognostic factors for OS and CSS in GBC patients. Subgroup analysis revealed that the survival hazard ratios (HRs) of NACT vs non-NACT for localized or locoregionally advanced GBC patients were significant in most subgroups. CONCLUSIONS: NACT may provide therapeutic benefits for localized or locoregionally advanced GBC patients, especially for those with advanced stage, node-positive, poorly differentiated or undifferentiated disease. NACT combined with radical surgery was associated with a survival advantage. Therefore, NACT combined with surgery may provide a better treatment option for resectable GBC patients.

Spin-Orbit-Locking Chiral Bound States in the Continuum.

Bound states in the continuum (BICs), which are confined optical modes exhibiting infinite quality factors and carrying topological polarization configurations in momentum space, have recently sparked significant interest across both fundamental and applied physics. Here, we show that breaking time-reversal symmetry by an external magnetic field enables a new form of chiral BICs with spin-orbit locking. Applying a magnetic field to a magneto-optical photonic crystal slab lifts doubly degenerate BICs into a pair of chiral BICs carrying opposite pseudospins and orbital angular momenta. Multipole analysis verifies the nonzero angular momenta and reveals the spin-orbital-locking behaviors. In momentum space, we observe ultrahigh quality factors and near-circular polarization surrounding chiral BICs, enabling potential applications in spin-selective nanophotonics. Compared to conventional BICs, the magnetically induced chiral BICs revealed here exhibit distinct properties and origins, significantly advancing the topological photonics of BICs by incorporating broken time-reversal symmetry.

Seismic response of mountain tunnel induced by fault slip.

With the rapid development of Chinese transportation networks, such as the Sichuan-Tibet railway, numerous tunnels are under construction or planned in mountainous regions. Some of these tunnels must traverse or be situated near active fault zones, which could suffer damage from fault slip. In this study, the seismic response of a mountain tunnel subjected to coseismic faulting was analyzed using a fault-structure system in a two-step process. Firstly, a nonuniform slip model was proposed to calculate the ground deformations and internal displacements induced by a specific active fault on a geological scale, considering nonuniform slips on the fault plane. The 1989 Loma Prieta and 2022 Menyuan earthquakes were chosen as case studies to validate the proposed slip model. Secondly, the calculated displacement of the Menyuan earthquake was used as the input load for the discrete-continuous coupling analysis of the Daliang tunnel on an engineering scale. The simulated deformation of the Daliang tunnel aligned with the on-site damage observations following the Menyuan earthquake. Lastly, the effects of different fault conditions on the tunnel seismic response were investigated. The results indicate that the distribution of the peak longitudinal strain of the lining is governed by fault mechanisms, and the degree of fault slip significantly influences the response of the tunnel. A tunnel passing through an active fault with a wider fault fracture zone and smaller dip angle experience less damage.

Suppression of NUPR1 in fibroblast-like synoviocytes reduces synovial fibrosis via the Smad3 pathway.

BACKGROUND: Synovial fibrosis is a common complication of knee osteoarthritis (KOA), a pathological process characterized by myofibroblast activation and excessive extracellular matrix (ECM) deposition. Fibroblast-like synoviocytes (FLSs) are implicated in KOA pathogenesis, contributing to synovial fibrosis through diverse mechanisms. Nuclear protein 1 (NUPR1) is a recently identified transcription factor with crucial roles in various fibrotic diseases. However, its molecular determinants in KOA synovial fibrosis remain unknown. This study aims to investigate the role of NUPR1 in KOA synovial fibrosis through in vivo and in vitro experiments. METHODS: We examined NUPR1 expression in the murine synovium and determined the impact of NUPR1 on synovial fibrosis by knockdown models in the destabilization of the medial meniscus (DMM)-induced KOA mouse model. TGF-ß was employed to induce fibrotic response and myofibroblast activation in mouse FLSs, and the role and molecular mechanisms in synovial fibrosis were evaluated under conditions of NUPR1 downexpression. Additionally, the pharmacological effect of NUPR1 inhibitor in synovial fibrosis was assessed using a surgically induced mouse KOA model. RESULTS: We found that NUPR1 expression increased in the murine synovium after DMM surgical operation. The adeno-associated virus (AAV)-NUPR1 shRNA promoted NUPR1 deficiency, attenuating synovial fibrosis, inhibiting synovial hyperplasia, and significantly reducing the expression of pro-fibrotic molecules. Moreover, the lentivirus-mediated NUPR1 deficiency alleviated synoviocyte proliferation and inhibited fibroblast to myofibroblast transition. It also decreased the expression of fibrosis markers α-SMA, COL1A1, CTGF, Vimentin and promoted the activation of the SMAD family member 3 (SMAD3) pathway. Importantly, trifluoperazine (TFP), a NUPR1 inhibitor, attenuated synovial fibrosis in DMM mice. CONCLUSIONS: These findings indicate that NUPR1 is an antifibrotic modulator in KOA, and its effect on anti-synovial fibrosis is partially mediated by SMAD3 signaling. This study reveals a promising target for developing novel antifibrotic treatment.

A novel chlorin derivative Shengtaibufen (STBF) mediated photodynamic therapy combined with iodophor for the treatment of chronic superficial leg wounds infected with methicillin-resistant Staphylococcus aureus: A retrospective clinical study.

OBJECTIVE: Chronic wounds are costly and difficult to treat, resulting in morbidity and even mortality in some cases due to a high methicillin-resistant Staphylococcus aureus (MRSA) burden contributing to chronicity. We aimed to observe the antimicrobial activity and healing-promoting effect of a novel photosensitizer Shengtaibufen (STBF)-mediated antibacterial photodynamic therapy (PDT) on MRSA-infected chronic leg ulcers. PATIENTS AND METHODS: This was a retrospective, comparative, single-center clinical study. A total of 32 patients with chronic lower limb wounds infected with MRSA from January 2022 to December 2023 were finally included in this study by searching the electronic medical records of the dermatology department of Huadong Hospital, including a group of red light combined with iodophor (control+iodophor, n=16, receiving red light once a week for 8 weeks and routine dressing change with iodophor once a day) and a group of STBF-mediated PDT (STBF-PDT) combined with iodophor (STBF-PDT+iodophor, n=16, receiving STBF-PDT and routine dressing change with iodophor once a day). STBF-PDT was performed once a week (1 mg/ml STBF, 1 h incubation, 630 nm red light, 80 J/cm2) for 8 weeks. The primary endpoints included wound clinical signs, wound size, wound-related pain, re-epithelialization score, MRSA load and wound-related quality of life (wound-QoL). Any adverse events were also recorded. RESULTS: We found that STBF-PDT+iodophor could effectively alleviate clinical infection symptoms, accelerate wound closure, reduce average biological burden and improve wound-QoL without severe adverse events in comparison to the control+iodophor group. The STBF-PDT+iodophor group obtained a mean percentage reduction of 65.22% in wound size (from 18.96±11.18 cm2 to 6.59±7.94 cm2) and excellent re-epithelialization scores, as compared with a decrease of 30.17% (from 19.23±9.80 cm2 to 13.43±9.32 cm2) for the control+iodophor group. Significant differences in wound area were observed at week 6 (p=0.028*) and week 8 (p=0.002**). The bacterial load decreased by 99.86% (from 6.45 × 107±2.69 × 107 to 8.94 × 104±1.92 × 105 CFU/cm2, p<0.0001) in the STBF-PDT+iodophor group and 1.82% (from 6.61 × 107±2.13 × 107 to 6.49 × 107±2.01 × 107 CFU/cm2, p=0.029) in the control+iodophor group. The wound-QoL in STBF-PDT+iodophor group had a 51.62% decrease in overall score (from 29.65±9.33 at the initial to 14.34±5.17 at week 8, p<0.0001) compared to those receiving red light and routine wound care (from 30.73±17.16 to 29.32±15.89 at week 8, p=0.003). Moreover, patients undergoing STBF-PDT+iodophor exhibited great improvements in all domains of wound-QoL (physical, psychological and everyday-life), whereas the control+iodophor group ameliorated in only one field (everyday-life). CONCLUSION: Our data confirmed that a novel photosensitizer, STBF-mediated PDT, when combined with iodophor, served as a potential modality for MRSA infection and a possible therapy for other drug-resistant microorganisms, and as a promising alternative for chronic cutaneous infectious diseases.

Revealing the nature of covalently tethered distonic radical anions in the generation of heteroatom-centered radicals: evidence for the polarity-matching PCET pathway.

Recognition of the intermediacy and regulation of reactivity patterns of radical intermediates in radical chemistry have profound impacts on harnessing and developing the full potential of open-shell species in synthetic settings. In this work, the possibility of in situ formation of O/N-X intermediates from Brønsted base covalently tethered carbonyl hypohalites (BCTCs) for the generation of heteroatom-centered radicals has certainly been excluded by NMR experiments and density functional theory calculations. Instead, the spectroscopic analyses reveal that the BCTCs serve as precursors of tether-tunable distonic radical anions (TDRAs) which have been unequivocally substantiated to be involved in the direct cleavage of O/N-H bonds to generate the corresponding heteroatom-centered radicals. Meanwhile, a deep insight into the properties and reactivities of the resulting TDRAs indicates that the introduction of a tethered Brønsted base on the parent open-shell species reinforces their stabilities and leads to a reversal of electrophilicity. Moreover, the dual descriptor values and electrophilicity indices are calculated based on eleven reported radical reactions involving various electrophilic/nucleophilic radical species, further confirming their validity in the prediction of the polar effect and the polarity-matching consistency between nucleophilic TDRAs and protic O/N-H bonds. The additional halogen-free experiments mediated by the combination of phthaloyl peroxide and TEMPO also prove the feasibility of the TDRA-assisted philicity-regulation approach. Lastly, detailed intrinsic bond orbital (IBO) and Hirschfeld spin population analyses are employed to elucidate that the H-atom abstraction processes are the polarity-matching proton-coupled electron transfer (PCET) pathways, with a degree of oxidative asynchronicity.

Danggui-Shaoyao-San protects against non-alcoholic steatohepatitis via modulation of hepatic APP protein, Lysosomal CTSB release, and NF-κB activation.

Background: Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play. Methods: UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining. Results: Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aß expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aß-induced Cathepsin B lysosomal release, reducing hepatic inflammation. Conclusion: Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.

PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors.

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles in vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles. Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry through testing six distinct chirally resolved linkers and a simple aliphatic linker. The structure activity relationships (SARs) of these linkers are examined extensively, beyond the conventional level, by characterizing the activation of all putative transducers over a 44 min time course. Our multiparametric analysis reveals previously unappreciated specific linker-dependent effects on primary pharmacophores, receptors, transducer activation kinetics, and bias, highlighting the utility of this comprehensive approach and the significance of the linker type in shaping transducer bias profiles.