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The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-β, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp. [ABSTRACT FROM AUTHOR]

DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD. [ABSTRACT FROM AUTHOR]

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1–277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1–277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1–277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD. [ABSTRACT FROM AUTHOR]

The aggregation of α‐synuclein plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Epidemiological evidence indicates that high level of homocysteine (Hcy) is associated with an increased risk of PD. However, the molecular mechanisms remain elusive. Here, we report that homocysteine thiolactone (HTL), a reactive thioester of Hcy, covalently modifies α‐synuclein on the K80 residue. The levels of α‐synuclein K80Hcy in the brain are increased in an age‐dependent manner in the TgA53T mice, correlating with elevated levels of Hcy and HTL in the brain during aging. The N‐homocysteinylation of α‐synuclein stimulates its aggregation and forms fibrils with enhanced seeding activity and neurotoxicity. Intrastriatal injection of homocysteinylated α‐synuclein fibrils induces more severe α‐synuclein pathology and motor deficits when compared with unmodified α‐synuclein fibrils. Increasing the levels of Hcy aggravates α‐synuclein neuropathology in a mouse model of PD. In contrast, blocking the N‐homocysteinylation of α‐synuclein ameliorates α‐synuclein pathology and degeneration of dopaminergic neurons. These findings suggest that the covalent modification of α‐synuclein by HTL promotes its aggregation. Targeting the N‐homocysteinylation of α‐synuclein could be a novel therapeutic strategy against PD. [ABSTRACT FROM AUTHOR]

Aims: Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting‐state fMRI and arterial spin labeling imaging. Methods: IGE patients and healthy participants underwent resting‐state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across‐voxel CBF‐DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio. Results: The study included 26 children with IGE and 35 sex‐ and age‐matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across‐voxel CBF‐DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group. Conclusion: Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE. [ABSTRACT FROM AUTHOR]

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare pancreatic tumor that accounts for <1% of all primary pancreatic malignant tumors. Although the tumor is considered a variant of pancreatic ductal adenocarcinoma, there are substantial differences in the clinicopathological characteristics between UCOGCP and pancreatic ductal adenocarcinoma. Imaging examinations are useful in making a correct diagnosis, and providing a reasonable and effective surgical treatment regimen; however, the imaging characteristics of UCOGCP require further investigation. The present report describes a rare case of UCOGCP with rapid progression and poor prognosis. The patient could not undergo surgery and received chemotherapy drugs only. Chemotherapy did not markedly improve the outcome, and a follow-up 6 months after discharge showed that the patient had died. The present report describes this case and summarizes the available imaging findings to increase awareness, and to improve early diagnosis of this rare disease and therapeutic outcomes. [ABSTRACT FROM AUTHOR]

The cultivation of students' intercultural communicative competence (ICC) is one of the main objectives of College English teaching in China. The present study aims to construct the Process-oriented intercultural teaching mode for promoting college students' ICC grounded in the current reality of cultural teaching in Chinese College English course and presents an empirical analysis of the effects of Process-oriented intercultural teaching in Chinese College English classroom. The results of the analysis indicate that the Process-oriented intercultural teaching is more effective than the traditional cultural teaching in enhancing the students' affective and behavioral dimensions of ICC and gained significantly higher satisfaction among teacher and students. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of this study was to explore the potential for vertical transmission of hepatitis B virus (HBV) from parents to offspring via human germ cells. METHODS For study samples, 250 oocytes from hepatitis B surface antigen (HBsAg) seropositive women and 578 embryos from couples with at least one HBsAg seropositive partner were collected. HBV DNA in the nuclei of oocytes and embryos was detected by fluorescence in situ hybridization; HBsAg expression was analysed using immunofluorescence; and serum HBV DNA levels were measured by real-time PCR. The HBV infection duration of the women and the serum HBsAg status of their mothers were also examined. RESULTS HBV DNA was present in 9.6% (24/250) of oocytes and 14.4% (83/578) of embryos. Rates of HBV DNA positive embryos were similar among couples in which the woman, man or both partners were HBsAg seropositive, 13.1% (57/436), 21.3% (16/75) and 14.9% (10/67), respectively. Rates of positivity in oocytes and embryos were significantly higher in a group with high serum levels HBV DNA than in a group with lower serum levels (P= 0.004 and P= 0.002, respectively). Higher rates of oocyte positivity were found for women whose mothers were HBV infected compared with those with uninfected mothers. Expression of HBsAg was observed in 8.7% (2/28) oocytes and 14.1% (10/71) embryos (P= 0.34). CONCLUSIONS The presence of HBV DNA in human oocytes or embryos was related to the women's serum levels of HBV DNA and the infection status of their mothers. The HBV positive embryos were either maternally or paternally dependent. HBV infection may result in vertical transmission to the offspring via germ cells. [ABSTRACT FROM PUBLISHER]