Lone-Star retractor perineal exposure method for laparoscopic abdominal perineal resection of rectal cancer.

BACKGROUND: The abdominal perineal resection (APR), historically referred to as Mile's procedure, stands as a time-honored surgical intervention for rectal cancer management. Advancements in surgical techniques and the advent of neoadjuvant therapies have significantly improved the rate of sphincter preservation among patients afflicted with rectal cancer, including those with ultralow rectal cancer. Despite these improvements, APR maintains its irreplaceable role in the clinical landscape, particularly for cases involving low rectal cancer with encroachment on the external anal sphincter or levator ani muscles. Optimal perineal exposure stands as a pivotal phase in APR, given that the precision of this maneuver is directly correlated with both the safety of the surgery and the patient's subsequent long-term prognosis. AIM: To evaluate the value of Lone-Star retractor (LSR) perineal exposure method in the treatment for laparoscopic APR of rectal cancer. METHODS: We reviewed the records of 38 patients with rectal cancer at Anqing Municipal Hospital from January 2020 to December 2023, including 20 patients who underwent the APR procedure with a LSR perineal exposure method (LSR group) and 18 patients who underwent the APR procedure with a conventional perineal exposure method (control group). In the LSR group, following incision of the skin and subcutaneous tissue, the LSR was placed and dynamically adjusted according to the surgical plane to fully expose the perineal operative field. RESULTS: A total of 38 patients underwent laparoscopic APR, none of whom were found to have distant metastasis upon intraoperative exploration. Perineal blood loss, the postoperative hospital stays and the wound pain scores in the LSR group were significantly lower than those in the control group. A single surgeon completed the perineal operation significantly more often in the LSR group than in the control group (P < 0.05). The incidence of infection via the perineal incision in the LSR group was significantly lower than that in the control group (P < 0.05). No cases of distant metastasis or local recurrence were found among the patients at the postoperative follow-up. CONCLUSION: The application of the LSR technique might be helpful for performing perineal exposure during APR for rectal cancer and could reduce the incidence of perineal complications, shorten the postoperative hospital stay, improve postoperative pain, and allow one surgeon to perform the perineal operation.

A MOFs/MIPs@GAs Ternary Composite Catalytic System with Graphene Oxide Aerogels as the Multifunctional Skeleton for High-Efficiency Detoxification of Organophosphate Nerve Agents in Pure Water.

Organophosphate nerve agents (OPs) are widely used as pesticides and chemical agents and pose a threat to human health and life. At present, most personal protective equipment usually only serves as physical protection and does not have an effect of chemical detoxification. In this work, ultra lightweight graphene oxide aerogels (GAs) have been used as a multifunctional skeleton to integrate the metal-organic frameworks (MOFs) and molecularly imprinted polymers (MIPs) together for obtaining a high-performance hybrid material (MOFs/MIPs@GAs) on hydrolysis detoxification of OPs. As a porous three-dimensional material full of carboxyl groups, GAs can not only support excellent mass transfer performance but also provide a proper pH self-buffering catalytic reaction external environment for hydrolyzing OPs. The obtained MOFs/MIPs@GAs can catalyze dimethyl-4-nitrophenyl phosphate (DMNP) hydrolysis detoxification rapidly in pure water (kobs = 0.2227 min-1, t1/2 = 3.11 min). This ternary hybrid material with exceptional performance and practical applicability has vast application prospects for the development of protective equipment.

Prognosis Analysis of Rat Liver Transplantation Under Direct Vision of Single Operator.

OBJECTIVE: This study aims to investigate the impact of surgical experimental variables on the prognosis of orthotopic liver transplantation (OLT) in rats, with the goal of enhancing the efficacy of modeling techniques. METHODS: Using Kamada's "two-cuff method" of rat orthotopic liver transplantation, 76 pairs of SD-Wistar rats were performed orthotopic liver transplantation from March to September 2023. Thirteen experimental factors during the perioperative period and the survival time of recipient rats were collected and recorded. To explore the surgical factors affecting the prognosis of rat liver transplantation and summarize the surgical techniques. RESULTS: The success rate of orthotopic liver transplantation in SD-Wistar rats was 68.4%, with 24 recipients surviving within 3-7 days and 28 recipients surviving more than 1 week. Donor liver perfusion, recipient blood loss, recipient liver blood expulsion, anhepatic phase, suprahepatic inferior vena cava anastomosis time and anesthesia recovery time are related to the survival of recipient rats after liver transplantation. Donor liver perfusion, eliminating blood in recipient liver and intraoperative blood loss of recipient are surgical factors affecting the prognosis of liver transplantation in rats. The survival time of recipient rats with liver perfusion through abdominal aorta, eliminating blood in recipient liver was relatively prolonged after operation. CONCLUSION: Under the condition of reasonable control of the anhepatic phase, the perfusion method of the donor liver, whether to eliminate blood in recipient liver, and intraoperative blood loss of recipient are important surgical factors affecting the prognosis of liver transplantation in rats.

CircRNA-Phf21a_0002 promotes pyroptosis to aggravate hepatic ischemia/ reperfusion injury by sponging let-7b-5p.

Hepatic ischemia‒reperfusion injury is a common injury in liver surgery and liver transplantation that can lead to liver function damage, including oxidative stress, apoptosis, autophagy and inflammatory reactions. Pyroptosis is a type of inflammatory programmed cell death that has been implicated in ischemia‒reperfusion injury-associated inflammatory reactions. Although circular RNAs can regulate cell death in hepatic ischemia‒reperfusion injury, their relationship with pyroptosis remains unclear. Therefore, this study aimed to investigate the effect of circular RNA on pyroptosis in hepatic ischemia‒reperfusion injury. We constructed a mouse hepatic ischemia‒reperfusion injury model for circular RNA sequencing and obtained 40 circular RNAs with significant differential expression, of which 39 were upregulated and 1 was downregulated. Subsequently, the endogenous competitive RNA network was constructed using TarBase, miRTarBase, TargetScan, RNAhybrid, and miRanda. Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology functional analyses of downstream target genes revealed that circRNA-Phf21a_0002 might affect pyroptosis by regulating the mTOR signaling pathway and Bach1 by sponging let-7b-5p. The overexpression plasmid upregulated the expression of circRNA-Phf21a_0002 in a hypoxia/reoxygenation model, which aggravated pyroptosis in AML12 cells and apoptosis and necrosis of hepatocytes. Next, we investigated the underlying mechanism and found that circRNA-Phf21a_0002 enabled the expression of Bach1 through sponging of let-7b-5p. The aggravation of pyroptosis via overexpression of circRNA-Phf21a_0002 was reversed by let-7b-5p mimics in hypoxia/reoxygenation-subjected AML12 cells. Collectively, our study clarifies that circRNA-Phf21a_0002 aggravates the pyroptosis of hepatocytes related to ischemia-reperfusion by sponging let-7b-5p. These findings provide new molecular mechanisms and novel biomarkers for follow-up treatment.

Visual training for the treatment of retinal photoreceptor inner and outer segment connection (IS/OS) fracture: A case report.

BACKGROUND: The inner segments and outer segments (IS/OS) of the retinal photoreceptors are the areas that receive light signals and are the most initial sites for generating visual impulses, and the integrity of the IS/OS has a direct impact on visual sensitivity. METHODS: We performed OCT on a 6-year-old child with vision loss and found that the cause of his vision loss was a retinal IS/OS fracture, and the child underwent some treatments to improve microcirculation and nourish the retina at a higher-level hospital, but his vision never improved. Our examination of this child revealed that this child not only had decreased visual acuity, but also hypermetropia, but his near stereopsis was normal. The symptoms were similar to those of amblyopia, so we tried to use visual training as a treatment. RESULTS: First, 6 sessions of fine visual stimulation were given, followed by 3 sessions of accommodation training, and we followed the 4 stages of accommodation training: perception of accommodation, amplitude of accommodation, sensitivity of accommodation, and autonomic accommodation. After 9 consecutive visual training sessions, the child's visual acuity was stabilized at 0.6, and then we added eye movement training, and after the child's visual acuity was improved to 0.7, we suppressed the visual acuity of the left eye to 0.6, so as to make the visual acuity of both eyes similar, which would promote the establishment of binocular stereo vision, and then we carried out 9 more visual training sessions, and the patient's visual acuity was stabilized at 0.8 gradually. OCT review showed that the child's retinal IS/OS fracture was basically closed. CONCLUSION SUBSECTIONS: In conclusion, our study found that visual training can restore visual acuity in children with monocular IS/OS fracture and also promote repair of IS/OS fracture, which increases our understanding and knowledge of the treatment of retinal IS/OS fracture, and this case may provide some lessons for the treatment of retinal IS/OS fracture in children. We hope to have more samples of retinal IS/OS fracture in the future to evaluate the efficacy of visual training for retinal IS/OS fracture.

SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia.

Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia's severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.

Inhibition of Dorsal Root Ganglia Transient Receptor Potential Ankyrin 1 Upregulation Contributes to the Protective Effect of Morphine Against Gastric Mucosal Damage Induced by Water-Immersion Restraint Stress.

The pathogenesis mechanism of acute gastric mucosal lesions (AGML) is still unclear; further exploration is urgently needed to find a new therapeutic target. This study aimed to investigate whether morphine might regulate the expression and function of transient receptor potential ankyrin 1 (TRPA1) through a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-dependent pathway, thereby alleviating gastric mucosal lesions caused by water-immersion restraint stress (WIRS). Rats were administered with intrathecal morphine, TRPA1 antagonist (HC-030031), µ-opioid receptor antagonist, or protein kinase A inhibitor (H-89), respectively, before WIRS. After 6 hours of WIRS, microscopic lesions, hematoxylin and eosin staining, and transmission electron microscopy were applied to assess the damage of the gastric mucosa. Real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were conducted to detect the levels of TRPA1 and substance P (SP) in the dorsal root ganglia (DRG) and gastric tissues. In addition, immunofluorescence was used to explore the possible co-expression of TRPA1 and µ-opioid receptors in the DRG. The results indicated that WIRS upregulated TRPA1 and SP in gastric mucosa, and HC-030031 or H-89 could alleviate gastric mucosal lesions caused by WIRS (P < .0001). Morphine was found to suppress both WIRS-induced gastric mucosal lesions (P < .0001) and the upregulation of TRPA1 (P = .0086) and SP (P = .0013). Both TRPA1 and SP play important roles in the pathogenesis of WIRS-induced AGML. Exogenous gastroprotective strategies reduce elevated levels of TRPA1 via the cAMP/PKA-dependent pathway. Inhibition of TRPA1 upregulation in the DRG is critical for intrathecal morphine preconditioning-induced gastric protection.

CGPA: multi-context insights from the cancer gene prognosis atlas.

Cancer transcriptomic data are used extensively to interrogate the prognostic value of targeted genes, yet basic scientists and clinicians have predominantly relied on univariable survival analysis for this purpose. This method often fails to capture the full prognostic potential and contextual relevance of the genes under study, inadvertently omitting a group of genes we term univariable missed-opportunity prognostic (UMOP) genes. Recognizing the complexity of revealing multifaceted prognostic implications, especially when extending the analysis to include various covariates and thresholds, we present the Cancer Gene Prognosis Atlas (CGPA). This platform greatly enhances gene-centric biomarker research across cancer types by offering an interactive and user-friendly interface for highly customized, in-depth prognostic analysis. CGPA notably supports data-driven exploration of gene pairs and gene-hallmark relationships, elucidating key composite biological mechanisms like synthetic lethality and immunosuppression. It further expands its capabilities to assess multi-gene panels using both public and user-provided data, facilitating a seamless mechanism-to-machine analysis. Additionally, CGPA features a designated portal for discovering prognostic gene modules using curated cancer immunotherapy data. Ultimately, CGPA's comprehensive, accessible tools allow cancer researchers, including those without statistical expertise, to precisely investigate the prognostic landscape of genes, customizing the model to fit specific research hypotheses and enhancing biomarker discovery and validation through a synergy of mechanistic and data-driven strategies.

Mendelian randomization study reveals causal effects of specific gut microbiota on the risk of interstitial cystitis/bladder pain syndrome (IC/BPS).

Evidence from previous studies have demonstrated that gut microbiota are closely associated with occurrence of interstitial cystitis/bladder pain syndrome (IC/BPS), yet the causal link between the two is not well known. In this study, we performed a two-sample Mendelian randomization (MR) analysis to determine the possible causal association between gut microbiota with IC/BPS. Gut microbiota summary level data were derived from the genome-wide association study (GWAS) conducted by MiBioGen and the IC/BPS GWAS summary level data were obtained from the GWAS Catalog. Next, we performed an MR study to investigate the causal link between gut microbiota and IC/BPS. The primary method for causal analysis was the inverse variance weighted (IVW), and the MR results were validated through multiple sensitivity analyses. A positive association was found between IC/BPS and eight gut microbial taxa, including genus Bacteroides, genus Haemophilus, genus Veillonella, genus Coprococcus1, genus Butyricimonas, family Bacteroidaceae, family Christensenellaceae, and order Lactobacillales. Sensitivity analysis revealed lack of significant pleiotropy or heterogeneity in the obtained results. This MR analysis reveals that a causal association exists between some gut microbiota with IC/BPS. This finding may is expected to guide future research and development of IC/BPS preventions and treatments based on the bladder-gut axis. However, given the clinical complexity and diagnostic challenges of IC/BPS, along with the limitations of using large-scale GWAS summary data for analysis, our MR results require further validation through additional research.

Peroxisome proliferator­activated receptor γ alleviates human umbilical vein endothelial cell injury in deep vein thrombosis by blocking endoplasmic reticulum stress.

The present study aimed to explore the role of peroxisome proliferator-activated receptor γ (PPARγ) in the development of deep vein thrombosis (DVT), as well as to discover the potential regulatory mechanism of PPARγ. Human umbilical vein endothelial cells (HUVECs) were treated with modified glycated human serum albumin (M-HSA) to mimic DVT. PPARγ expression and activity were detected using western blot analysis and the corresponding activity detection kit, respectively. Cell Counting Kit-8 and the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays were employed to detect cell viability and apoptosis, respectively. The levels of thrombosis-related factors and inflammatory cytokines were detected by ELISA. The levels of oxidative stress-related factors were determined by the corresponding commercial kits. In addition, tunicamycin (TM), the agonist of endoplasmic reticulum stress (ERS), was applied to investigate the potential mechanism. The results indicated that M-HSA caused reduced expression and activity of PPARγ in HUVECs; these effects were reversed by PPARγ overexpression, which significantly inhibited M-HSA-induced cell viability loss, cell apoptosis, inflammation and oxidative stress in HUVECs. In addition, ERS was activated following M-HSA stimulation in HUVECs, but was suppressed by PPARγ overexpression. Furthermore, TM partly abolished the protective role of PPARγ overexpression against cell viability loss, cell apoptosis, inflammation and oxidative stress in M-HSA-induced HUVECs. In summary, PPARγ antagonized M-HSA-induced HUVEC injury by suppressing the activation of ERS, which provides a novel strategy for the treatment of DVT.

Solid pseudopapillary neoplasm of the pancreas with hepatic metastases: problems and strategies.

Background: Solid pseudopapillary neoplasms of the pancreas with hepatic metastases are infrequent and difficult to diagnose, and treatment is uncertain. Methods: A retrospective analysis of clinical data from patients with pancreatic solid pseudopapillary neoplasm (SPN) hepatic metastases who underwent surgery at the First Hospital of Jilin University from January 2005 to December 2021 was conducted. A total of 287 patients with SPN were included in the study, of which 8 (3%) developed liver metastases, all of whom were treated surgically and recovered well after surgery. The clinical presentation, imaging features, surgical treatment, histopathological examination, and postoperative follow-up data (mean 70 months; range 28-138 months) of the patients were recorded and analyzed. Clinical response strategies can be derived by reviewing previous studies on hepatic metastases of SPNs. Results: For resectable hepatic metastases from pancreatic solid pseudopapillary neoplasms, early surgery with total resection of the primary tumor and metastasis has shown great efficiency and is associated with patient good prognosis. In patients presenting unresectable hepatic metastases, aggressive tumor reduction surgery resulted in the alleviation of clinical symptoms and reduction of tumor burden while potentially achieving long-term survival. Conclusion: For hepatic metastases of SPNs, a preoperative liver tissue biopsy is beneficial for a definitive diagnosis. Surgery demonstrates excellent therapeutic efficacy and is considered the preferred curative treatment approach. This paper presents clinical experiences with SPN-related hepatic metastases at the Affiliated Hospital of Jilin University, which can be used to guide patient counseling in clinical practice.

Steering the Site Distance of Atomic Cu-Cu Pairs by First-Shell Halogen Coordination Boosts CO2-to-C2 Selectivity.

Electrocatalytic reduction of CO2 into C2 products of high economic value provides a promising strategy to realize resourceful CO2 utilization. Rational design and construct dual sites to realize the CO protonation and C-C coupling to unravel their structure-performance correlation is of great significance in catalysing electrochemical CO2 reduction reactions. Herein, Cu-Cu dual sites with different site distance coordinated by halogen at the first-shell are constructed and shows a higher intramolecular electron redispersion and coordination symmetry configurations. The long-range Cu-Cu (Cu-I-Cu) dual sites show an enhanced Faraday efficiency of C2 products, up to 74.1%, and excellent stability. In addition, the linear relationships that the long-range Cu-Cu dual site is accelerated to C2H4 generation and short-range Cu-Cu (Cu-Cl-Cu) dual site is beneficial for C2H5OH formation are disclosed. In situ electrochemical attenuated total reflection surface enhanced infrared absorption spectroscopy, in situ Raman and theoretical calculations manifest that long-range Cu-Cu dual sites can weaken reaction energy barriers of CO hydrogenation and C-C coupling, as well as accelerating deoxygenation of *CH2CHO. This study uncovers the exploitation of site-distance-dependent electrochemical property to steer the CO2 reduction pathway, as well as a potential generic tactic to target C2 synthesis by constructing the desired Cu-Cu dual sites.

Crossmodal sensory neurons based on high-performance flexible memristors for human-machine in-sensor computing system.

Constructing crossmodal in-sensor processing system based on high-performance flexible devices is of great significance for the development of wearable human-machine interfaces. A bio-inspired crossmodal in-sensor computing system can perform real-time energy-efficient processing of multimodal signals, alleviating data conversion and transmission between different modules in conventional chips. Here, we report a bio-inspired crossmodal spiking sensory neuron (CSSN) based on a flexible VO2 memristor, and demonstrate a crossmodal in-sensor encoding and computing system for wearable human-machine interfaces. We demonstrate excellent performance in the VO2 memristor including endurance (>1012), uniformity (0.72% for cycle-to-cycle variations and 3.73% for device-to-device variations), speed (<30 ns), and flexibility (bendable to a curvature radius of 1 mm). A flexible hardware processing system is implemented based on the CSSN, which can directly perceive and encode pressure and temperature bimodal information into spikes, and then enables the real-time haptic-feedback for human-machine interaction. We successfully construct a crossmodal in-sensor spiking reservoir computing system via the CSSNs, which can achieve dynamic objects identification with a high accuracy of 98.1% and real-time signal feedback. This work provides a feasible approach for constructing flexible bio-inspired crossmodal in-sensor computing systems for wearable human-machine interfaces.

The impacts of sex and the 5xFAD model of Alzheimer's disease on the sleep and spatial learning responses to feeding time.

Introduction: The relationships between the feeding rhythm, sleep and cognition in Alzheimer's disease (AD) are incompletely understood, but meal time could provide an easy-to-implement method of curtailing disease-associated disruptions in sleep and cognition. Furthermore, known sex differences in AD incidence could relate to sex differences in circadian rhythm/sleep/cognition interactions. Methods: The 5xFAD transgenic mouse model of AD and non-transgenic wild-type controls were studied. Both female and male mice were used. Food access was restricted each day to either the 12-h light phase (light-fed groups) or the 12-h dark phase (dark-fed groups). Sleep (electroencephalographic/electromyographic) recording and cognitive behavior measures were collected. Results: The 5xFAD genotype reduces NREM and REM as well as the number of sleep spindles. In wild-type mice, light-fed groups had disrupted vigilance state amounts, characteristics, and rhythms relative to dark-fed groups. These feeding time differences were reduced in 5xFAD mice. Sex modulates these effects. 5xFAD mice display poorer spatial memory that, in female mice, is curtailed by dark phase feeding. Similarly, female 5xFAD mice have decreased anxiety-associated behavior. These emotional and cognitive measures are correlated with REM amount. Discussion: Our study demonstrates that the timing of feeding can alter many aspects of wake, NREM and REM. Unexpectedly, 5xFAD mice are less sensitive to these feeding time effects. 5xFAD mice demonstrate deficits in cognition which are correlated with REM, suggesting that this circadian-timed aspect of sleep may link feeding time and cognition. Sex plays an important role in regulating the impact of feeding time on sleep and cognition in both wild-type and 5xFAD mice, with females showing a greater cognitive response to feeding time than males.

Hot Electrons Induced by Localized Surface Plasmon Resonance in Ag/g-C3N4 Schottky Junction for Photothermal Catalytic CO2 Reduction.

Converting carbon dioxide (CO2) into high-value-added chemicals using solar energy is a promising approach to reducing carbon dioxide emissions; however, single photocatalysts suffer from quick the recombination of photogenerated electron-hole pairs and poor photoredox ability. Herein, silver (Ag) nanoparticles featuring with localized surface plasmon resonance (LSPR) are combined with g-C3N4 to form a Schottky junction for photothermal catalytic CO2 reduction. The Ag/g-C3N4 exhibits higher photocatalytic CO2 reduction activity under UV-vis light; the CH4 and CO evolution rates are 10.44 and 88.79 µmol·h-1·g-1, respectively. Enhanced photocatalytic CO2 reduction performances are attributed to efficient hot electron transfer in the Ag/g-C3N4 Schottky junction. LSPR-induced hot electrons from Ag nanoparticles improve the local reaction temperature and promote the separation and transfer of photogenerated electron-hole pairs. The charge carrier transfer route was investigated by in situ irradiated X-ray photoelectron spectroscopy (XPS). The three-dimensional finite-difference time-domain (3D-FDTD) method verified the strong electromagnetic field at the interface between Ag and g-C3N4. The photothermal catalytic CO2 reduction pathway of Ag/g-C3N4 was investigated using in situ diffuse reflectance infrared Fourier transform spectra (DRIFTS). This study examines hot electron transfer in the Ag/g-C3N4 Schottky junction and provides a feasible way to design a plasmonic metal/polymer semiconductor Schottky junction for photothermal catalytic CO2 reduction.

Achieving Regioselectivity for Remote C-H Activation by Substructure Conformations: an Approach of Paralogous Cytochrome P450 Enzymes.

For advanced synthetic intermediates or natural products with multiple unactivated and energetically similar C(sp3)-H bonds, controlling regioselectivity for the C-H activation is particularly challenging. The use of cytochrome P450 enzymes (CYPs) is a promising solution to the 'regioelectivity' challenge in remote C-H activation. Notably, CYPs and organic catalysts share a fundamental principle: they strive to control the distance and geometry between the metal reaction center and the target C-H site. Most structural analyses of the regioselectivity of CYPs are limited to the active pocket, particularly when explaining why regioselectivity could be altered by enzyme engineering through mutagenesis. However, the substructures responsible for forming the active pocket in CYPs are well known to display complex dynamic changes and substrate-induced plasticity. In this context, we highlight a comparative study of the recently reported paralogous CYPs, IkaD and CftA, which achieve different regioselectivity towards the same substrate ikarugamycin by distinct substructure conformations. We propose that substructural conformation-controlled regioselectivity might also be present in CYPs of other natural product biosynthesis pathways, which should be considered when engineering CYPs for regioselective modifications.

Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood.

In this study, we explore the possibility of inferring characteristics of the tumor immune microenvironment from the blood. Specifically, we investigate two datasets of patients with head and neck squamous cell carcinoma with matched single-cell RNA sequencing (scRNA-seq) from peripheral blood mononuclear cells (PBMCs) and tumor tissues. Our analysis shows that the immune cell fractions and gene expression profiles of various immune cells within the tumor microenvironment can be inferred from the matched PBMC scRNA-seq data. We find that the established exhausted T-cell signature can be predicted from the blood and serve as a valuable prognostic blood biomarker of immunotherapy response. Additionally, our study reveals that the inferred ratio between tumor memory B- and regulatory T-cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. These results highlight the promising potential of PBMC scRNA-seq in cancer immunotherapy and warrant, and will hopefully facilitate, further investigations on a larger scale. The code for predicting tumor immune microenvironment from PBMC scRNA-seq, TIMEP, is provided, offering other researchers the opportunity to investigate its prospective applications in various other indications. SIGNIFICANCE: Our work offers a new and promising paradigm in liquid biopsies to unlock the power of blood single-cell transcriptomics in cancer immunotherapy.

Pectolinarigenin targeting FGFR3 alleviates osteoarthritis progression by regulating the NF-κB/NLRP3 inflammasome pyroptotic pathway.

OBJECTIVE: Osteoarthritis (OA) is a chronic degenerative disease characterized by cartilage degeneration, involving inflammation, pyroptosis, and degeneration of the extracellular matrix (ECM). Pectolinarigenin (PEC) is a natural flavonoid with antioxidant, anti-inflammatory and anti-tumor properties. This study aims to explore the potential of PEC in ameliorating OA progression and its underlying mechanisms. METHODS: Chondrocytes were exposed to 10 ng/mL IL-1ß to simulate OA-like changes. The effect of PEC on IL-1ß-treated chondrocytes was assessed using ELISA, western blot, and immunofluorescence. The mRNA sequencing (mRNA-seq) was employed to explore the possible targets of PEC in delaying OA progression. The OA mouse model was induced through anterior cruciate ligament transection (ACLT) and divided into sham, ACLT, ACLT+5 mg/kg PEC, and ACLT+10 mg/kg PEC groups. Micro-computed tomography and histological analysis were conducted to confirm the beneficial effects of PEC on OA in vivo. RESULTS: PEC mitigated chondrocyte pyroptosis, as evidenced by reduced levels of pyroptosis-related proteins. Additionally, PEC attenuated IL-1ß-mediated chondrocyte ECM degradation and inflammation. Mechanistically, mRNA-seq showed that FGFR3 was a downstream target of PEC. FGFR3 silencing reversed the beneficial effects of PEC on IL-1ß-exposed chondrocytes. PEC exerted anti-pyroptotic, anti-ECM degradative, and anti-inflammatory effects through upregulating FGFR3 to inhibit the NF-κB/NLRP3 pyroptosis-related pathway. Consistently, in vivo experiments demonstrated the chondroprotective effects of PEC in OA mice. CONCLUSION: PEC alleviate OA progression by FGFR3/NF-κB/NLRP3 pathway mediated chondrocyte pyroptosis, ECM degradation and inflammation, suggesting the potential of PEC as a therapeutic agent for OA.

Drug-Free "Triboelectric Immunotherapy" Activating Immunity for Osteomyelitis Treatment and Recurrence Prevention.

Treatment of osteomyelitis is clinically challenging with low therapeutic efficacy and high risk of recurrence owing to the immunosuppressive microenvironment. Existing therapies are limited by drug concentration and single regulatory effect on the immune network, and emphasize the role of anti-inflammatory effects in reducing osteoclast rather than the role of proinflammatory effects in accelerating infection clearance, which is not conducive to complete bacteria elimination and recurrence prevention. Herein, a direct-current triboelectric nanogenerator (DC-TENG) is established to perform antibacterial effects and modulate immunological properties of infectious microenvironments of osteomyelitis through electrical stimulation, namely triboelectric immunotherapy. Seeing from the results, the triboelectric immunotherapy successfully activates polarization to proinflammatory (M1) macrophages in vitro, accompanied by satisfying direct antibacterial effects. The antibacterial and osteogenic abilities of triboelectric immunotherapy are verified in rat cranial osteomyelitis models. The effects on the polarization and differentiation of immune-related cells in vivo are investigated by establishing in situ tibial osteomyelitis models and immunosurveillance models in C57 mice respectively, indicating the ability of activating immunity and producing immunological memory for in situ infection and secondary recurrence, thus accelerating healing and preventing relapse. This study provides an efficient, long-acting, multifunctional, and wearable triboelectric immunotherapy strategy for drug-free osteomyelitis treatment systems.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.