Novel 6-amino-1,3,5-triazine derivatives as potent BTK inhibitors: structure-activity relationship (SAR) analysis and preliminary mechanism investigation.

Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of B-cell related malignancies. Irreversible inhibition of BTK by a covalent inhibitor has been proved to be a clinically effective therapy. However, most irreversible BTK inhibitors also inhibit other kinases including JAK3 and EGFR, leading to some adverse events. Herein, we reported the structure-based design and optimization of a series of irreversible BTK inhibitors bearing the 6-amino-1,3,5-triazine scaffold. Most of the synthesized compounds demonstrated considerable BTK inhibition and improved anti-proliferative activity against Raji and Ramos cells. Among them, compound C11 exhibited potent BTK inhibition (BTK IC50 = 17.0 nM) and a desirable selectivity profile especially over EGFR. Moreover, C11 effectively blocked activation of BTK and downstream signaling, arrested the cell cycle in G0/G1 phase and induced apoptosis in Raji cells. Its irreversible binding mode was further investigated by both molecular modeling and a washout experiment. Collectively, C11 is a novel selective irreversible BTK inhibitor worthy of further in-depth research.

Excess palmitate induces decidual stromal cell apoptosis via the TLR4/JNK/NF-kB pathways and possibly through glutamine oxidation.

During gestation, excess palmitate (PA) is enriched in decidua. Both excess PA and decidual dysfunctions are associated with numerous adverse pregnancy outcomes such as gestational diabetes, preeclampsia and preterm birth and intrauterine growth restriction. Here, mRNA data about the effects of PA were collected from multiple databases and analyzed. Human decidual tissues were obtained from clinically normal pregnancies, terminated for non-medical reasons, during the first trimester, and decidual stromal cells (DSCs) were isolated and exposed to PA, alone or together with the inhibitors of Toll-like receptor 4 (TLR4), Jun N-terminal kinase (JNK), nuclear factor-kappa-gene binding (NF-kB) or glutamine (GLN) oxidation. Furthermore, DSCs were transfected with lentiviral particles overexpressing human TLR4. We demonstrate that excess PA interacting with its receptor TLR4 disturbs DSC hemostasis during the first trimester. Specifically, high PA signal induced DSC apoptosis and formed an inflammatory program (elevated interleukin-1 beta and decreased interleukin-10) via the activation of TLR4/JNK/NF-kB pathways. A complexed cross-talk was found between TLR4/JNK/NF-kB signals and PA deposition in DSCs. Besides, under an excess PA environment, GLN oxidation was significantly enhanced in DSCs and the suppression of GLN oxidation further augmented PA-mediated DSC apoptosis and inflammatory responses. In conclusion, excess PA induces apoptosis and inflammation in DSCs via the TLR4/JNK/NF-kB pathways, which can be augmented by the suppression of GLN oxidation.

IL-2 and IL-27 synergistically promote growth and invasion of endometriotic stromal cells by maintaining the balance of IFN-γ and IL-10 in endometriosis.

Immune cells and cytokines have important roles in the pathogenesis of endometriosis. However, the production and role of cytokines of T helper type 1 (Th1) and Th2 cells in the progress of endometriosis have remained to be fully elucidated. The present study reported that the interferon (IFN)-γ levels and the percentage of IFN-γ+CD4+ cells were significantly increased in the peritoneal fluid (PF) at the early stage and maintained at a higher level at the advanced stage of endometriosis; furthermore, interleukin (IL)-10 and IL-10+CD4+ cells were elevated in the advanced stage of endometriosis. In addition, IL-2 levels in the PF at the advanced stage of endometriosis were elevated and negatively associated with IFN-γ expression. In a co-culture system of ectopic endometrial stromal cells (ESCs) and macrophages, elevated IL-2 was observed, and treatment with cytokines IL-2 and transforming growth factor-ß led to upregulation of the ratio of IL-2+ macrophages. IL-27-overexpressing ESCs and macrophages were able to induce a higher ratio of IL-10+CD4+ T cells. Blocking of IL-2 with anti-IL-2 neutralizing antibody led to upregulation of the ratio of IFN-γ+CD4+ T cells in the co-culture system in vitro. Recombinant human IL-10 and IFN-γ promoted the viability, invasiveness and transcription levels of matrix metalloproteinase (MMP)2, MMP9, and prostaglandin-endoperoxide synthase 2 of ESCs, particularly combined treatment with IL-10 and IFN-γ. These results suggest that IL-2 and IL-27 synergistically promote the growth and invasion of ESCs by modulating the balance of IFN-γ and IL-10 and contribute to the progress of endometriosis.

The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-ß.

The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors in vitro were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1ß, IL-10 and transforming growth factor (TGF)-ß in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor ß neutralizing antibody (αhIL-10Rß) or αTGF-ß could partly reverse these effects of ESCs and macrophages on NK cells in vitro These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-ß, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.

A multiplex CRISPR/Cas9 platform for fast and efficient editing of multiple genes in Arabidopsis.

The recently developed CRISPR/Cas9 system is a promising technology for targeted genome editing in a variety of species including plants. However, the first generation systems were designed to target one or two gene loci at a time. We designed a new multiplex CRISPR/Cas9 system that allows the co-expression of six sgRNA modules in one binary vector using a simple (three steps) cloning strategy in Arabidopsis. The transcription of the sgRNA modules is under the control of three different RNA Polymerase III-dependent promoters. We tested the efficiency of the new multiplex system by targeting six of the fourteen PYL families of ABA receptor genes in a single transformation experiment. One line with mutations in all six targeted PYLs was identified from 15 T1 plants. The mutagenesis frequency for the six individual PYL targets in the T1 lines ranged from 13 to 93 %. In the presence of ABA, the transgenic line identified as containing mutations in all six PYL genes produced the highest germination rate in the T2 progeny (37 %). Among these germinated seedlings, half of the analyzed plants (15/30) were homozygous mutants for at least four targeted genes and two plants (6.7 %) contained homozygous mutations in five of the targeted PYLs and the other targeted PYL had biallelic mutations. Homozygous sextuple mutants were identified in the T3 progeny and characterized together with previously described triple and sextuple PYL mutants. We anticipate that the application of this multiplex CRISPR/Cas9 system will strongly facilitate functional analysis of genes pathways and families.

Noninvasive imaging of aortic atherosclerosis by ultrasound biomicroscopy in a mouse model.

OBJECTIVES: The noninvasive and accurate evaluation of vessel characteristics in mouse models has become an intensive focus of vascular medicine. This study aimed to apply ultrasound biomicroscopy to evaluate aortic atherosclerotic progression in a low-density lipoprotein receptor (LDL-R) knockout mouse model of atherosclerosis. METHODS: Ten male LDL-R(-/-)C57BL/6 mice aged 16 and 24 weeks and 8 male wild-type C57BL/6 mice aged 16 and 24 weeks were used as experimental and control groups, respectively. Ultrasound biomicroscopy was applied to detect the morphologic characteristics of the aortic root, ascending aorta, aortic arch, and carotid artery and to measure the aortic root intima-media thickness and carotid artery bifurcation. RESULTS: Ultrasound biomicroscopy showed a significant increase in the aortic root intima-media thickness from 0.10 ± 0.03 mm in 16-week-old mice to 0.16 ± 0.04 mm in 24-week-old mice (P < .01). The ultrasound biomicroscopically measured intima-media thickness was highly correlated with the histologic measurement (r = 0.81). CONCLUSIONS: Ultrasound biomicroscopy could be used for a noninvasive, accurate, and dynamic analysis of aortic atherosclerosis in LDL-R knockout mice.

Discovery and Proof of Concept of Potent Dual Polθ/PARP Inhibitors for Efficient Treatment of Homologous Recombination-Deficient Tumors.

DNA polymerase theta (Polθ) has recently emerged as a new attractive synthetic lethal target involved in DNA damage repair. Inactivating Polθ alone or in combination with PARP inhibitors has demonstrated substantial therapeutic potential against tumors with homologous recombination (HR) defects such as alternation of BRCA genes. Herein, we report the design and proof of concept of a highly potent dual Polθ/PARP inhibitor 25d, which exhibited low nanomolar inhibitory activities against both Polθ and PARP1. Compared to combination treatment, 25d demonstrated superior antitumor efficacy in both MDA-MB-436 cells and xenografts by inducing more DNA damage and apoptosis. Importantly, 25d retained sensitivity in PARP inhibitor-resistant MDA-MB-436 cells with 53BP1 defect. Altogether, these findings illustrate the potential advantages of 25d, a first-in-class dual Polθ/PARP inhibitor, over monotherapy in treating HR-deficient tumors, including those with acquired PARP inhibitor resistance.

Structure-Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer.

Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment for patients expressing the constitutively active AR splice variants, such as AR-V7. Herein, we report the structure-activity relationship studies of 55 N-heterocycle-substituted hydantoins, which identified the structural motifs required for AR/AR-V7 degradation. Among them, the most potent compound 27c exhibited selective AR/AR-V7 degradation over other hormone receptors and excellent antiproliferative activities in LNCaP and 22RV1 cells. RNA sequence analysis confirmed that 27c effectively suppressed transcriptional activity of the AR signaling pathway. Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.

Targeting a mTOR/autophagy axis: a double-edged sword of rapamycin in spontaneous miscarriage.

Immune dysfunction is a primary culprit behind spontaneous miscarriage (SM). To address this, immunosuppressive agents have emerged as a novel class of tocolytic drugs, modulating the maternal immune system's tolerance towards the embryo. Rapamycin (PubChem CID:5284616), a dual-purpose compound, functions as an immunosuppressive agent and triggers autophagy by targeting the mTOR pathway. Its efficacy in treating SM has garnered significant research interest in recent times. Autophagy, the cellular process of self-degradation and recycling, plays a pivotal role in numerous health conditions. Research indicates that autophagy is integral to endometrial decidualization, trophoblast invasion, and the proper functioning of decidual immune cells during a healthy pregnancy. Yet, in cases of SM, there is a dysregulation of the mTOR/autophagy axis in decidual stromal cells or immune cells at the maternal-fetal interface. Both in vitro and in vivo studies have highlighted the potential benefits of low-dose rapamycin in managing SM. However, given mTOR's critical role in energy metabolism, inhibiting it could potentially harm the pregnancy. Moreover, while low-dose rapamycin has been deemed safe for treating recurrent implant failure, its potential teratogenic effects remain uncertain due to insufficient data. In summary, rapamycin represents a double-edged sword in the treatment of SM, balancing its impact on autophagy and immune regulation. Further investigation is warranted to fully understand its implications.

Interactions between soybean ABA receptors and type 2C protein phosphatases.

The plant hormone abscisic acid (ABA) plays important roles in regulating plant growth, development, and responses to environmental stresses. Proteins in the PYR/PYL/RCAR family (hereafter referred to as PYLs) are known as ABA receptors. Since most studies thus far have focused on Arabidopsis PYLs, little is known about PYL homologs in crop plants. We report here the characterization of 21 PYL homologs (GmPYLs) in soybean. Twenty-three putative GmPYLs can be found from soybean genome sequence and categorized into three subgroups. GmPYLs interact with AtABI1 and two GmPP2Cs in diverse manners. A lot of the subgroup I GmPYLs interact with PP2Cs in an ABA-dependent manner, whereas most of the subgroup II and III GmPYLs bind to PP2Cs in an ABA-independent manner. The subgroup III GmPYL23, which cannot interact with any of the tested PP2Cs, differs from other GmPYLs. The CL2/gate domain is crucial for GmPYLs-PP2Cs interaction, and a mutation in the conserved proline (P109S) abolishes the interaction between GmPYL1 and AtABI1. Furthermore, the ABA dependence of GmPYLs-PP2Cs interactions are partially correlated with two amino acid residues preceding the CL2/gate domain of GmPYLs. We also show that GmPYL1 interacts with AtABI1 in an ABA-dependent manner in plant cells. Three GmPYLs differentially inhibit AtABI1 and GmPP2C1 in an ABA-dependent or -enhanced manner in vitro. In addition, ectopically expressing GmPYL1 partially restores ABA sensitivity of the Arabidopsis triple mutant pyr1/pyl1/pyl4. Taken together, our results suggest that soybean GmPYLs are ABA receptors that function by interacting and inhibiting PP2Cs.

Changes in Phytochemical Content, Antioxidant Activity, and Anti-Inflammatory Properties of Cudrania tricuspidata Fruits Treated by Roasting.

The study investigated the antioxidant effects of roasted Cudrania tricuspidata (C. tricuspidata) fruits by comparing them with unroasted C. tricuspidata fruits. The results showed that the roasted C. tricuspidata fruits (150 °C, 120 min) exhibited significantly higher antioxidant activity, especially in terms of anti-inflammatory effects, than the unroasted fruits. Interestingly, there is a high correlation between the color of the roasted fruit and the antioxidant activity. Heating disrupts cells and deactivates endogenous oxidative enzymes, leading to an increase in flavonoid content. Moreover, heat treatment may also interfere with plant metabolism, thereby influencing flavonoid content. Moreover, an HPLC analysis of roasted fruits in our study showed that the increase in antioxidant activity was attributed to the increase in flavan-3-ols and phenolic acids in the roasted C. tricuspidata fruits. To the best of our knowledge, this is the first time the antioxidant activity and anti-inflammation of roasted C. tricuspidata fruits was studied. The study concluded that roasted C. tricuspidata fruits could be a valuable natural source of antioxidants for various food and medicinal applications.

Optimizing the Fermentation Conditions of Cudrania tricuspidata Fruit Using Bacillus amyloliquefaciens for Anti-Inflammatory Activity and GC-MS-Based Volatile Component Characteristics.

The aim of this study is to optimize the performance conditions used for maximum anti-inflammatory activity and to clarify in vitroanti-inflammatory properties of fermented C. tricuspidata fruit. Based on the single-factor experiment and Box-Behnken design, the optimized fermentation conditions of C. tricuspidata fruit for maximum anti-inflammatory activity were 3.8 d fermentation period, 8.4% (v/w) inoculation concentration, and 29.2°C fermentation temperature. Under optimal conditions, anti-inflammatory activity-based nitric oxide of fermented C. tricuspidata fruit reached 93.9%. Moreover, this study provides a theoretical basis and experimental data containing ß-hexosaminidase and reactive oxygen species for the medical use and industrialization of C. tricuspidata fruit fermentation. Interestingly, the results of GC-MS analysis confirmed that fermented C. tricuspidata fruits detect volatile components different from unfermented C. tricuspidata fruits. We suggested that this volatile component may have been involved in the anti-inflammatory reaction, but scientific verification of this is needed later. Therefore, an in-depth study of volatile components detected from fermented C. tricuspidata fruits will need to be conducted later.

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage.

Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of FOLR2+ macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.

Dietary supplementation of solubles from shredded, steam-exploded pine particles modifies gut length and cecum microbiota in cyclic heat-stressed broilers.

This study was conducted to investigate the effect of supplementing solubles from steam-exploded pine particles (SSPP) on mitigating the adverse effects of cyclic heat stress (CHS) in broilers which were distributed into 3 dietary treatment groups and 2 temperature conditions. Heat stress (HS) exposure for 6 h daily for 7 d adversely affected performance parameters and rectal temperature of chickens. The absolute and relative weights of the liver and bursa of Fabricius decreased in the CHS group while the relative lengths of the jejunum and ileum increased, which was rescued by dietary supplementation with SSPP. The expression of mucin2 (MUC2) and occludin (OCLN) genes was decreased in CHS birds. The expression of heat shock protein -70 and -90 increased in 0% HS compared to that in 0% NT. Birds supplemented with 0.4% SSPP had higher NADPH oxidase -1 expression than birds in the 0% and 0.1% SSPP treatments. Beta diversity of gut microbiota evaluated through unweighted UniFrac distances was significantly different among treatments. Bacteroidetes was among the 2 most abundant phyla in the cecum, which decreased with 0.1% NT and increased with 0.1% HS in comparison to 0% NT. A total of 13 genera were modified by HS, 5 were altered by dose, and nine showed an interaction effect. In conclusion, CHS adversely affects performance and gut health which can be mitigated with dietary SSPP supplementation that modifies the cecal microbiota in broilers.

Dietary supplementation of solubles from shredded, steam-exploded pine particles modulates cecal microbiome composition in broiler chickens.

This study evaluated the effects of supplementing solubles from shredded, steam-exploded pine particles (SSPP) on growth performances, plasma biochemicals, and microbial composition in broilers. The birds were reared for 28 days and fed basal diets with or without the inclusion of SSPP from 8 days old. There were a total of three dietary treatments supplemented with 0% (0% SSPP), 0.1% (0.1% SSPP) and 0.4% (0.4% SSPP) SSPP in basal diets. Supplementation of SSPP did not significantly affect growth or plasma biochemicals, but there was a clear indication of diet-induced microbial shifts. Beta-diversity analysis revealed SSPP supplementation-related clustering (ANOSIM: r = 0.31, p < 0.01), with an overall lower (PERMDISP: p < 0.05) individual dispersion in comparison to the control group. In addition, the proportions of the Bacteroides were increased, and the relative abundances of the families Vallitaleaceae, Defluviitaleaceae, Clostridiaceae, and the genera Butyricicoccus and Anaerofilum (p < 0.05) were significantly higher in the 0.4% SSPP group than in the control group. Furthermore, the linear discriminant analysis effect size (LEfSe) also showed that beneficial bacteria such as Ruminococcus albus and Butyricicoccus pullicaecorum were identified as microbial biomarkers of dietary SSPP inclusion (p < 0.05; | LDA effect size | > 2.0). Finally, network analysis showed that strong positive correlations were established among microbial species belonging to the class Clostridia, whereas Erysipelotrichia and Bacteroidia were mostly negatively correlated with Clostridia. Taken together, the results suggested that SSPP supplementation modulates the cecal microbial composition of broilers toward a "healthier" profile.

A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives.

Prostate cancer (PC), the second most prevalent malignancy in men worldwide, has been proven to depend on the aberrant activation of androgen receptor (AR) signaling. Long-term androgen deprivation for the treatment of PC inevitably leads to castration-resistant prostate cancer (CRPC) in which AR remains a crucial oncogenic driver. Thus, there is an urgent need to develop new strategies to address this unmet medical need. Targeting AR for degradation has recently been in a vigorous development stage, and accumulating clinical studies have highlighted the benefits of AR degraders in CRPC patients. Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure-activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.

An innovative coupling technique for integrating oil spill prediction model with finite volume method-based ocean model.

Marine oil spill pollution have increased recent years, threatening the safety of the marine environment. This paper proposes a coupling technique: Fast Mapping & Addressing(FMA) that integrates the oil spill model with oceanographic model. The FMA technique is based on hash function and spatial quadtree algorithm to achieve efficient addressing from an unstructured to a structured grid. The oil spill model simulates the oil spill process, while the ocean model simulates the ocean currents. The efficiency is improved about ten times compared to the interpolation algorithm. Results reveal the difference between the simulation results of the ocean model and the measured data is minimal, with an MAE(Mean Absolute Error) and RMSE(Root Mean Square Error) of about 0.06 m. Moreover, two oil spill events in China's nearshore were selected to simulate and verify the results. Indeed, our model's results agree with the observed data, demonstrating that our model can achieve a satisfied simulation of oil spill.

miR-148b-3p, as a tumor suppressor, targets son of sevenless homolog 1 to regulate the malignant progression in human osteosarcoma.

Osteosarcoma (OS) is a malignant tumor that occurs in children and adolescents. Previous studies reported a low expression of miR-148b-3p in OS, but its biological function in OS remains obscure. This study aimed to explore the role of miR-148b-3p in OS progression. Herein, the expression of miR-148b-3p and son of sevenless homolog 1 (SOS1) both in OS tissues and cells were examined using quantitative real-time polymerase chain reaction and Western blotting assay. miR-148b-3p mimic or inhibitor, pcDH-SOS1 plasmid or si-SOS1 and agomir-miR-148b-3p were constructed for cell transfection. In vitro, the biological effect of miR-148b-3p was determined employing MTT, EdU, colony formation, flow cytometry, transwell and wound healing assay, separately. The target relationship between SOS1 3'-untranslated region (3'-UTR) and miR-148b-3p was analyzed using dual-luciferase reporter gene. In vivo, the inhibition of agomir-miR-148b-3p in mice was evaluated via a xenograft mouse model. miR-148b-3p was noticeably low-expressed in OS tissues and cells, and miR-148b-3p over-expression in OS cells suppressed the growth, migration and invasion, induced apoptosis. The effect of miR-148b-3p-inhibitor on cell biological behavior is opposite to that of miR-148b-3p over-expression. Conversely, The expression of SOS1 was significant higher in OS tissues and cells, miR-148b-3p targeted and was negatively associated with the expression level of SOS1. In addition, the anti-tumor effect of miR-148b-3p was reversed by SOS1. Importantly, we demonstrated that the tumor growth of stably over-expressed miR-148b-3p human MG-63 cells was obviously reduced in tumor-bearing mice. These data highlighted that miR-148b-3p might be as a promising therapeutic target for OS.

Mesh plug erosion into the small intestine after inguinal hernia repair: A case report.

BACKGROUND: Mesh plug (MP) erosion into the intra-abdominal organs is a rare but serious long-term complication after inguinal hernia repair (IHR), and may lead to aggravation of symptoms if not treated promptly. It is difficult to diagnose MP erosion as there are no obvious specific clinical manifestations, and surgery is often needed for confirmation. In recent years, with the increased understanding of postoperative complications, MP eroding into the intra-abdominal organs has been a cause for concern among surgeons. CASE SUMMARY: A 50-year-old man was referred to the Department of General Surgery with the complaint of abdominal pain in the right lower quadrant for 2 d. He had a surgical history of right open IHR and partial thyroidectomy performed 20 years and 15 years ago, respectively. Computed tomography revealed a circinate high-density image with short segmental thickening of the ileum stuck to the abdominal wall, and no evidence of recurrent inguinal hernia. Laparoscopic abdominal exploration confirmed adhesion of the middle segmental portion of the ileal loop to the right inguinal abdominal wall; the rest of the small intestine was normal. Further exploration revealed migration of the polypropylene MP into the intraperitoneal cavity and formation of granulation tissue around the plug, which eroded the ileum. Partial resection of the ileum, including the MP and end-to-side anastomosis with an anastomat, was performed. CONCLUSION: Surgeons should aim to improve their ability to predict patients at high risk for MP erosion after IHR.

Intersex goats show different gene expression levels in the hypothalamus and pituitary compared with non-intersex goats based on RNA-Seq.

The conditions for sex reversal in vertebrate species have been extensively studied, and the results highlighted numerous key factors involved in sex differentiation. However, the transcriptomes in hypothalamic and pituitary tissues from intersex goats have rarely been studied. The aim of this study was to screen candidate genes and signalling pathways related to sex reversal in Huai goats by analyzing gene expression in hypothalamic and pituitary tissues via transcriptome sequencing and bioinformatics analyses. In total, 612 and 139 differentially expressed genes (DEGs) were identified between the intersex and non-intersex groups in the hypothalamus and pituitary, respectively. The DEGs in the hypothalamus and pituitary were significantly enriched in 41 and 16 signalling pathways, respectively, including the calcium signalling pathway, neuroactive ligand-receptor interaction signalling pathway, and oestrogen signalling pathway, which might be related to intersex sex development disorders. A candidate gene from the tachykinin family (TACR1) was significantly enriched in the calcium signalling pathway. Thirty-one DEGs were shared between these two comparisons and were enriched in several acetyl-CoA-related processes and the oestrogen signalling pathway. The results of the real-time PCR analysis show that the transcriptome sequencing results were reliable. The transcriptome data indicate that the regulation of various physiological systems is involved in intersex goat development. Therefore, these results provide helpful data enhancing our understanding of the molecular mechanisms underlying intersex syndrome in goats.