Predicting Outcome of Patients With Cerebral Hemorrhage Using a Computed Tomography-Based Interpretable Radiomics Model: A Multicenter Study.

OBJECTIVE: The aim of this study was to develop and validate an interpretable and highly generalizable multimodal radiomics model for predicting the prognosis of patients with cerebral hemorrhage. METHODS: This retrospective study involved 237 patients with cerebral hemorrhage from 3 medical centers, of which a training cohort of 186 patients (medical center 1) was selected and 51 patients from medical center 2 and medical center 3 were used as an external testing cohort. A total of 1762 radiomics features were extracted from nonenhanced computed tomography using Pyradiomics, and the relevant macroscopic imaging features and clinical factors were evaluated by 2 experienced radiologists. A radiomics model was established based on radiomics features using the random forest algorithm, and a radiomics-clinical model was further trained by combining radiomics features, clinical factors, and macroscopic imaging features. The performance of the models was evaluated using area under the curve (AUC), sensitivity, specificity, and calibration curves. Additionally, a novel SHAP (SHAPley Additive exPlanations) method was used to provide quantitative interpretability analysis for the optimal model. RESULTS: The radiomics-clinical model demonstrated superior predictive performance overall, with an AUC of 0.88 (95% confidence interval, 0.76-0.95; P < 0.01). Compared with the radiomics model (AUC, 0.85; 95% confidence interval, 0.72-0.94; P < 0.01), there was a 0.03 improvement in AUC. Furthermore, SHAP analysis revealed that the fusion features, rad score and clinical rad score, made significant contributions to the model's decision-making process. CONCLUSION: Both proposed prognostic models for cerebral hemorrhage demonstrated high predictive levels, and the addition of macroscopic imaging features effectively improved the prognostic ability of the radiomics-clinical model. The radiomics-clinical model provides a higher level of predictive performance and model decision-making basis for the risk prognosis of cerebral hemorrhage.

PagKNAT2/6b promotes shoot branching by attenuating auxin-strigolactone signalling in poplar.

Shoot branching from axillary bud (AB) directly determines plant architecture. However, the mechanism through which AB remains dormant or emerges to form branches as plants grow remains largely unknown. Here, the auxin-strigolactone (IAA-SL) pathway was first shown to regulate shoot branching in poplar, and we found that PagKNAT2/6b could modulate this pathway. PagKNAT2/6b was expressed mainly in the shoot apical meristem and AB and was induced by shoot apex damage. PagKNAT2/6b overexpressing poplar plants (PagKNAT2/6b OE) exhibited multiple branches that mimicked the branching phenotype of nontransgenic plants after decapitation treatment, while compared with nontransgenic controls, PagKNAT2/6b antisense transgenic poplar and Pagknat2/6b mutant lines exhibited a significantly decreased number of branches after shoot apex damage treatment. In addition, we found that PagKNAT2/6b directly inhibits the expression of the key IAA synthesis gene PagYUC6a, which is specifically expressed in the shoot apex. Moreover, overexpression of PagYUC6a in the PagKNAT2/6b OE background reduced the number of branches after shoot apex damage treatment. Overall, we conclude that PagKNAT2/6b responds to shoot apical injury and regulates shoot branching through the IAA-SL pathway. These findings may provide a theoretical basis and candidate genes for genetic engineering to create new forest tree species with different crown types.

Peiminine ameliorates Crohn's disease-like colitis by enhancing the function of the intestinal epithelial barrier through Nrf2/HO1 signal.

BACKGROUND AND AIMS: Impaired intestinal barrier function is key in maintaining intestinal inflammation in Crohn's disease (CD). However, no targeted treatment in clinical practice has been developed. Peiminine (Pm) strongly protects the epithelial barrier, the purpose of this study is to investigate whether Pm affects CD-like colitis and potential mechanisms for its action. METHODS: Trinitro-benzene-sulfonic acid (TNBS)-induced mice and Il-10-/- mice were used as CD animal models. Colitis symptoms, histological analysis, and intestinal barrier permeability were used to assess the Pm's therapeutic effect on CD-like colitis. The colon organoids were induced by TNF-α to evaluate the direct role of Pm in inhibiting apoptosis of the intestinal epithelial cells. Western blotting and small molecule inhibitors were used to investigate further the potential mechanism of Pm in inhibiting apoptosis of intestinal epithelial cells. RESULTS: Pm treatment reduced body weight loss, disease activity index (DAI) score, and inflammatory score, demonstrating that colonic inflammation in mice were alleviated. Pm decreased the intestinal epithelial apoptosis, improved the intestinal barrier function, and prevented the loss of tight junction proteins (ZO1 and claudin-1) in the colon of CD mice and TNF-α-induced colonic organoids. Pm activated Nrf2/HO1 signaling, which may protect intestinal barrier function. CONCLUSIONS: Pm inhibits intestinal epithelial apoptosis in CD mice by activating Nrf2/HO1 pathway. This partially explains the potential mechanism of Pm in ameliorating intestinal barrier function in mice and provides a new approach to treating CD.

PagJAZ5 regulates cambium activity through coordinately modulating cytokinin concentration and signaling in poplar.

Wood is resulted from the radial growth paced by the division and differentiation of vascular cambium cells in woody plants, and phytohormones play important roles in cambium activity. Here, we identified that PagJAZ5, a key negative regulator of jasmonate (JA) signaling, plays important roles in enhancing cambium cell division and differentiation by mediating cytokinin signaling in poplar 84K (Populus alba × Populus glandulosa). PagJAZ5 is preferentially expressed in developing phloem and cambium, weakly in developing xylem cells. Overexpression (OE) of PagJAZ5m (insensitive to JA) increased cambium activity and xylem differentiation, while jaz mutants showed opposite results. Transcriptome analyses revealed that cytokinin oxidase/dehydrogenase (CKXs) and type-A response regulators (RRs) were downregulated in PagJAZ5m OE plants. The bioactive cytokinins were significantly increased in PagJAZ5m overexpressing plants and decreased in jaz5 mutants, compared with that in 84K plants. The PagJAZ5 directly interact with PagMYC2a/b and PagWOX4b. Further, we found that the PagRR5 is regulated by PagMYC2a and PagWOX4b and involved in the regulation of xylem development. Our results showed that PagJAZ5 can increase cambium activity and promote xylem differentiation through modulating cytokinin level and type-A RR during wood formation in poplar.

A survey of breastfeeding among women with previous surgery for benign breast disease: a descriptive exploratory study.

BACKGROUND: Surgery is the primary treatment for benign breast disease and causes some disruption to the normal physiology of the breast, even when this disruption is localised, it remains unclear whether it affects women's ability to breastfeed. There are only a few studies describing the experience of breastfeeding in women who have undergone benign breast disease (BBD) surgery. METHODS: We retrospectively analysed data from patients aged 20-40 years in Guangdong, China, who underwent breast lumpectomy for BBD in our department between 01 January 2013 and 30 June 2019, with a follow-up date of 01 February 2022. Patients were included who had a history of childbirth between the time of surgery and the follow-up date. By collecting general information about this group of patients and information about breastfeeding after surgery, we described the breastfeeding outcomes of women of a fertile age who had previously undergone surgery for benign breast disease. RESULTS: With a median follow-up of 5.9 years, a total of 333 patients met the inclusion criteria. From the breastfeeding data of the first child born postoperatively, the mean duration of 'exclusive breastfeeding' was 5.1 months, and the mean duration of 'any breastfeeding' was 8.8 months. The rate of 'ever breastfeeding' is 91.0%, which is lower than the national average of 93.7%, while the exclusive breastfeeding rate at six months was 40.8%, was higher than the 29.2% national average. The any breastfeeding rate at 12 months was 30.0%, which was well below the 66.5% national average. The common reason for early breastfeeding cessation was insufficient breast milk. A total of 29.0% of patients who had ever breastfed after surgery voluntarily reduced the frequency and duration of breastfeeding on the operated breast because of the surgery. CONCLUSIONS: There are some impacts of BBD surgery on breastfeeding and some may be psychological. Institutions should provide more facilities for mothers who have undergone breast surgery to help them breastfeed, such as conducting community education on breastfeeding after breast surgery, training professional postoperative lactation consultants in hospitals, and extending maternity leave. Families should encourage mothers to breastfeed with both breasts instead of only the non-operated breast.

Simultaneously Engineering Oxygen Defects and Heterojunction into Ho-Doped ZnO Nanoflowers for Enhancing n-Propanol Gas Detection.

Lung cancer poses a serious threat to people's lives and health due to its high incidence rate and high mortality rate, making it necessary to effectively conduct early screening. As an important biomarker for lung cancer, the detection of n-propanol gas suffers from a low response value and a high detection limit. In this paper, flower-like Ho-doped ZnO was fabricated by the coprecipitation method for n-propanol detection at subppm concentrations. The gas sensor based on the 3% Ho-doped ZnO showed selectivity to n-propanol gas. Its response value to 100 ppm n-propanol was 341 at 140 °C, and its limit of detection (LOD) was about 25.6 ppb, which is lower than that of n-propanol in the breath of a healthy person (150 ppb). The calculation results show that the adsorption of n-propanol on a Ho-doped ZnO surface releases more energy than isopropanol, ethanol, formaldehyde, acetone, and ammonia. The enhanced gas-sensing properties of the Ho-doped ZnO material can be attributed to the fact that the Ho-doping distorts the crystal lattice of the ZnO, increases the specific surface area, and generates a large amount of oxygen defects. In addition, the doped Ho partially forms a Ho2O3/ZnO heterojunction in the material and improves the gas-sensing properties. The 3% Ho-doped ZnO material is expected to be a promising candidate for the trace detection of n-propanol gas.

Variant-specific antibody response following repeated SARS-CoV-2 vaccination and infection.

The ongoing emergence of SARS-CoV-2 variants poses challenges to the immunity induced by infections and vaccination. We conduct a 6-month longitudinal evaluation of antibody binding and neutralization of sera from individuals with six different combinations of vaccination and infection against BA.5, XBB.1.5, EG.5.1, and BA.2.86. We find that most individuals produce spike-binding IgG or neutralizing antibodies against BA.5, XBB.1.5, EG.5.1, and BA.2.86 2 months after infection or vaccination. However, compared to ancestral strain and BA.5 variant, XBB.1.5, EG.5.1, and BA.2.86 exhibit comparable but significant immune evasion. The spike-binding IgG and neutralizing antibody titers decrease in individuals without additional antigen exposure, and <50% of individuals neutralize XBB.1.5, EG.5.1, and BA.2.86 during the 6-month follow-up. Approximately 57% of the 107 followed up individuals experienced an additional infection, leading to improved binding IgG and neutralizing antibody levels against these variants. These findings provide insights into the impact of SARS-CoV-2 variants on immunity following repeated exposure.

Unraveling novel umami peptides from yeast extract (Saccharomyces cerevisiae) using peptidomics and molecular interaction modeling.

Yeast extract is increasingly becoming an attractive source for unraveling novel umami peptides that are healthier and more nutritious than traditional seasonings. In the present study, a strategy for screening novel umami peptides was established using mass spectrometry-based peptidomics combined with molecular interaction modeling, emphasizing on smaller peptides than previously reported. Four representative novel umami peptides of FE, YDQ, FQEY, and SPFSQ from yeast extract (Saccharomyces cerevisiae) were identified and validated by sensory evaluation, with thresholds determined as 0.234 ± 0.045, 0.576 ± 0.175, 0.327 ± 0.057 and 0.456 ± 0.070 mmol/L, respectively. Hydrogen and ionic bonds were the main characteristic interactions between the umami peptides and the well-recognized receptor T1R1/T1R3, in which Asp 110, Thr 112, Arg 114, Arg 240, Lys 342, and Glu 264 were the key sites in ligand-receptor recognition. Our study provides accurate sequences of umami peptides and molecular interaction mechanism for the umami effect.

Complanatuside A ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway.

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.

High-Efficiency Effect-Directed Analysis Leveraging Five High Level Advancements: A Critical Review.

Organic contaminants are ubiquitous in the environment, with mounting evidence unequivocally connecting them to aquatic toxicity, illness, and increased mortality, underscoring their substantial impacts on ecological security and environmental health. The intricate composition of sample mixtures and uncertain physicochemical features of potential toxic substances pose challenges to identify key toxicants in environmental samples. Effect-directed analysis (EDA), establishing a connection between key toxicants found in environmental samples and associated hazards, enables the identification of toxicants that can streamline research efforts and inform management action. Nevertheless, the advancement of EDA is constrained by the following factors: inadequate extraction and fractionation of environmental samples, limited bioassay endpoints and unknown linkage to higher order impacts, limited coverage of chemical analysis (i.e., high-resolution mass spectrometry, HRMS), and lacking effective linkage between bioassays and chemical analysis. This review proposes five key advancements to enhance the efficiency of EDA in addressing these challenges: (1) multiple adsorbents for comprehensive coverage of chemical extraction, (2) high-resolution microfractionation and multidimensional fractionation for refined fractionation, (3) robust in vivo/vitro bioassays and omics, (4) high-performance configurations for HRMS analysis, and (5) chemical-, data-, and knowledge-driven approaches for streamlined toxicant identification and validation. We envision that future EDA will integrate big data and artificial intelligence based on the development of quantitative omics, cutting-edge multidimensional microfractionation, and ultraperformance MS to identify environmental hazard factors, serving for broader environmental governance.

Two new oleanane triterpenes from Maytenus hookeri.

Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36-3.44 µM.

Magnolin inhibits intestinal epithelial cell apoptosis alleviating Crohn's disease-like colitis by suppressing the PI3K/AKT signalling pathway.

BACKGROUND AND AIMS: Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. METHODS: Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. RESULTS: The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. CONCLUSIONS: MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD.

Isolation and differential structure characteristics of calcium-binding peptides derived from Pacific cod bones by hydroxyapatite affinity.

Calcium-chelating peptides were found in Pacific cod bone, but their binding structure and properties have not been elucidated. Novel calcium-binding peptides were isolated by hydroxyapatite affinity chromatography (HAC), and their binding structure and properties were investigated by isothermal titration calorimetry (ITC), multispectral techniques, and mass spectrometry. Based on multiple purifications, the calcium binding capacity (CBC) of Pacific cod bone peptides (PBPs) was increased from 1.71 ± 0.15 µg/mg to 7.94 ± 1.56 µg/mg. Peptides with a molecular weight of 1-2 kDa are closely correlated with CBC. After binding to calcium, the secondary structure of peptides transitioned from random coil to ß-sheet, resulting in a loose and porous microstructure. Hydrogen bonds, electrostatic interaction, and hydrophobic interaction contribute to the formation of peptide­calcium complexes. The F21 contained 42 peptides, with repeated "GE" motif. Differential structure analysis provides a theoretical basis for the targeted preparation of high CBC peptides.

Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo.

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

Sclareol protected against intestinal barrier dysfunction ameliorating Crohn's disease-like colitis via Nrf2/NF-B/MLCK signalling.

BACKGROUND: Inflammation-induced intestinal barrier dysfunction is not only a pathological feature of Crohn's disease (CD) but also an important therapeutic target. Sclareol (SCL) is a nontoxic natural plant compound with anti-inflammatory effect, but its role in CD has not been established. METHODS: In vivo studies of mice with TNBS-induced colitis were carried out to evaluate the effects of SCL on CD-like colitis and intestinal barrier function. In vitro, a TNF-α-induced colonic organoid model was established to test the direct effect of SCL on inflammation-induced intestinal barrier injure and inflammatory response. The Nrf2/NF-κB/MLCK signalling was analysed to explore the mechanism of SCL. RESULTS: In vivo, SCL largely alleviated the colitis in TNBS mice, as evidenced by improvements in the weight loss, colitis symptoms, endoscopic score, macroscopic histological score, and histological inflammation score. Moreover, SCL significantly improved intestinal barrier dysfunction, manifested as reduced intestinal permeability and decreased intestinal bacterial translocation in TNBS mice. Importantly, SCL antagonised the intestinal mucosal inflammation while protecting tight junctions in TNBS mice. In vitro, SCL largely depressed pro-inflammatory cytokines levels and improved intestinal epithelial permeability in a TNF-α-induced colonic organoid model. In the context of CD, the protective effects of SCL against inflammation and intestinal barrier damage are at least partially results from the Nrf2 signalling activation and the NF-κB/MLCK signalling inhibition. CONCLUSIONS: SCL improved intestinal barrier dysfunction and alleviated CD-like colitis, possibly through modulation of Nrf2/NF-κB/MLCK signalling. In view of SCL's safety profile, there is hope that it will be useful in the clinic.

Biomimetic Frustrated Lewis Pair Catalysts for Hydrogenation of CO to Methanol at Low Temperatures.

The industrial production of methanol through CO hydrogenation using the Cu/ZnO/Al2O3 catalyst requires harsh conditions, and the development of new catalysts with low operating temperatures is highly desirable. In this study, organic biomimetic FLP catalysts with good tolerance to CO poison are theoretically designed. The base-free catalytic reaction contains the 1,1-addition of CO into a formic acid intermediate and the hydrogenation of the formic acid intermediate into methanol. Low-energy spans (25.6, 22.1, and 20.6 kcal/mol) are achieved, indicating that CO can be hydrogenated into methanol at low temperatures. The new extended aromatization-dearomatization effect involving multiple rings is proposed to effectively facilitate the rate-determining CO 1,1-addition step, and a new CO activation model is proposed for organic catalysts.

A Multifunctional CaII-EuIII Heterometallic Organic Framework with Sensing and Selective Adsorption in Water.

With increasing global industrialization, it is urgent and challenging to develop multifunctional species for detection and adsorption in the environment. For this purpose, a novel anionic heterometallic organic framework, [(CH3)2NH2][CaEu(CAM)2(H2O)2]·4H2O·4DMF (CaEuCAM), is hydrothermally synthesized based on chelidamic acid (H3CAM). Single crystal analysis shows that CaEuCAM features two different oxygen-rich channels along the c-axis in which one CAM3- bridges two sextuple-coordinated Ca2+ and two octuple-coordinated Eu3+ with a µ4-η1: η1: η1: η1: η1: η1 new chelating and bridging mode. The characteristic bright red emission and superior hydrostability of CaEuCAM under harsh acidic and basic conditions benefit it by acting as a highly sensitive sensor for Fe3+ and 3-nitrophenol (3-NP) with extremely low LODs through remarkable quenching. The combination of experiments and theoretical calculations for sensing mechanisms shows that the competitive absorption and interaction are responsible for Fe3+-induced selective emission quenching, while that for 3-NP is the result of the synergism of host-guest chemistry and the inner filter effect. Meanwhile, the assimilation of negative charge plus channels renders CaEuCAM a highly selective adsorbent for methylene blue (MB) due to a synergy of electrostatic affinity, ion-dipole interaction, and size matching. Of note is the reusability of CaEuCAM toward Fe3+/3-NP sensing and MB adsorption besides its fast response. These findings could be very useful in guiding the development of multifunctional Ln-MOFs for sensing and adsorption applications in water media.

Cytological, Physiological, and Transcriptomic Analyses of the Leaf Color Mutant Yellow Leaf 20 (yl20) in Eggplant (Solanum melongena L.).

Leaf color mutants are ideal materials for studying chlorophyll metabolism, chloroplast development, and photosynthesis in plants. We discovered a novel eggplant (Solanum melongena L.) mutant yl20 (yellow leaf 20) that exhibits yellow leaves. In this study, we compared the leaves of the mutant yl20 and wild type (WT) plants for cytological, physiological, and transcriptomic analyses. The results showed that the mutant yl20 exhibits abnormal chloroplast ultrastructure, reduced chlorophyll and carotenoid contents, and lower photosynthetic efficiency compared to the WT. Transcriptome data indicated 3267 and 478 differentially expressed genes (DEGs) between WT and yl20 lines in the cotyledon and euphylla stages, respectively, where most DEGs were downregulated in the yl20. Gene Ontology (GO) analysis revealed the "plastid-encoded plastid RNA polymerase complex" and the "chloroplast-related" terms were significantly enriched. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that the significantly enriched DEGs were involved in flavone and flavonol biosynthesis, porphyrin and chlorophyll metabolism, etc. We speculated that these DEGs involved in significant terms were closely related to the leaf color development of the mutant yl20. Our results provide a possible explanation for the altered phenotype of leaf color mutants in eggplant and lay a theoretical foundation for plant breeding.

Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury.

ABSTRACT: Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.

Neurobiological basis of emergence from anesthesia.

The suppression of consciousness by anesthetics and the emergence of the brain from anesthesia are complex and elusive processes. Anesthetics may exert their inhibitory effects by binding to specific protein targets or through membrane-mediated targets, disrupting neural activity and the integrity and function of neural circuits responsible for signal transmission and conscious perception/subjective experience. Emergence from anesthesia was generally thought to depend on the elimination of the anesthetic from the body. Recently, studies have suggested that emergence from anesthesia is a dynamic and active process that can be partially controlled and is independent of the specific molecular targets of anesthetics. This article summarizes the fundamentals of anesthetics' actions in the brain and the mechanisms of emergence from anesthesia that have been recently revealed in animal studies.