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Netrin‐1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age‐dependent protease that cuts human alpha‐synuclein (α‐Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α‐SNCA transgenic mice in an age‐dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin‐1 levels. Netrin‐1 deprivation in primary cultures induces AEP and caspase‐3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin‐1 deprivation‐elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP‐truncated UNC5C intracellular fragment strongly elicits α‐Syn aggregation and dopaminergic loss, locomotor deficits in α‐SNCA transgenic mice. Hence, the findings demonstrate that netrin‐1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose. To investigate the correlation between sonographic and computed tomography and pathological features of basal cell adenomas (BCAs) of the parotid gland. Methods. This retrospective study included 41 patients (43 tumors) with BCAs. The tumors were divided into three types based on their location in the parotid gland and their imaging features. The features of the tumors were analyzed. Results. Imaging manifestations and corresponding pathological results of most BCAs of the parotid glands resembled those of benign parotid gland tumors. Malignant transformation occurred in membranous BCAs and in those with extensive cribriform structures. Type-II and type-III tumors accounted for 82.93% of the total proportion. Thirteen tumors showed cystic degeneration with 30.23%, among which type-III tumors could easily develop cystic degeneration. These cystic areas might correspond to cystic degeneration or focal necrosis. Cystic change was not dependent on the tumor size. The pathological features of the tumors were correlated to their imaging manifestations. Conclusion. Most BCAs of the parotid glands have imaging manifestations similar to those of benign parotid gland tumors. BCAs with extensive cribriform structures and of the membranous type can show malignant transformation and should be treated with caution in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The accessory spleen has no anatomical or vascular relationship with the normal spleen, The tissue structure and physiological function of the accessory spleen are the same as those of the normal spleen, which usually locate in the splenic hilum and the tail of the pancreas. The aims of this manuscript are to present a rare case of the gastric accessory spleen and a review of the literature.Case Presentation: A 19-year-old male patient was sent to the emergency department with stomach bleeding after drinking alcohol. The computed tomographic scan showed a 1.2 cm × 1.7 cm mass at the lesser curvature of the gastric fundus. Gastrointestinal endoscopy displayed a submucosal elevated lesion on the gastric fundus, and gastrectomy was performed. Postoperative pathological examination proved an accessory spleen in the stomach. The postoperative course was uneventful, and the patient was discharged on the 6th day after the surgery.Conclusions: The accessory spleen at the fundus of stomach is extremely rare, especially in this case, which is accompanied by acute gastric bleeding, and it is difficult to diagnosis before operation. Many literatures reported that it was misdiagnosis as tumor, so it is necessary to diagnose accessory spleen correctly. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Objective To evaluate the clinical effect of Tension-free laparoscopic lateral suspension with mesh for pelvic organ prolapse. Methods A total of 85 patients who underwent pelvic organ prolapse were selected as the study group, and 40 patients underwent Laparoscopic sacral fixation surgery(LSC) as the control group in Henan Provincial People's Hospital from March 1, 2021 to October 31, 2023. The patients were divided into two subgroups' uterine preservation group and uterine resection group and followed up until April 30, 2024. The intraoperative conditions and postoperative complications were recorded and analyzed. POP quantitative staging(POP-Q) scores were used for evaluation. Preoperative and postoperative quality of life and therapeutic effect were evaluated using the pelvic floor distress inventory short form-20(PFDI-20), urinary distress inventory-6 (UDI-6), colorectalanal distress inventory-8 (CRADI-8), pelvic organ prolapse distress inventory-6(POPDI-6), pelvic floor impact questionnaire-7(PFIQ-7), prolapse and Incontinence sexual function questionnaire short form(PISQ-12). Results The median follow-up time for patients in the study group is 13.13 months, with an objective cure rate of 96.47% and a reoperation rate of 1.18%. The perioperative complication rates are 6.45% for uterine resection and 4.35% for uterine preservation, while the mesh exposure rate is 1.61% for uterine resection. In comparison, the median follow-up time for patients in the control group is slightly longer at 13.76 months, with an objective cure rate of 92.5% and a reoperation rate of 2.5%. The perioperative complication rates are higher at 14.71% for uterine resection and as high as 33.33% for uterine preservation, while the mesh exposure rate is also elevated at 8.82% for uterine resection. Despite these differences, there was no significant disparity in objective cure rates or reoperation rates between the study group and the control group. Furthermore, it was observed that the study group experienced shorter operation times, less bleeding, faster postoperative recovery, shorter hospitalization periods, lower perioperative complications, and reduced mesh exposure rates -especially among patients with uterine preservation. Additionally, intra-group comparisons revealed significant improvements in all POP-Q indicators one year after surgery (P < 0.05), along with significantly lower scores on PFDI-20, UDI-6, CRADI-8, POPDI-6, PFIQ-7, and PISQ-12 scales compared to pre-surgery levels (P < 0.05). However, no significant inter-group differences were noted. Conclusions Tension-free laparoscopic lateral suspension with mesh proves to be an effective surgical approach for treating anteriorand middle pelvic organ prolapse. It demonstrates few perioperative complications while significantly improving prolapse symptoms and enhancing patient qualityof life. It stands as a viable alternative to sacrocolpopexy, particularly beneficial for patients with a preserved uterus. [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 eutrophication problem now threatens many lakes and reservoirs. To avoid the occurrence of algal blooms, some cities try to increase the flow rate or directly choose lakes or reservoirs with a short water residence time (WRT) as drinking water sources. However, up to now, whether such a strategy can achieve its goal is still unclear. In this study, a newly restored lake with a WRT of approximately 3 days was chosen to investigate algal growth potential as well as its responses to external nitrogen (N) and phosphorus (P) inputs. The results suggested that although the water quality of the lake could generally meet the environmental quality standards for surface water, dissolved inorganic nitrogen reached a high level with an average value of 1.58 mg/L. Meanwhile, a considerable increase in Chl- a concentration was observed across the flow direction. Especially, in July, Chl- a concentration at the site near the outlet was 8.1 times higher than that at the inlet, and cyanobacteria became the dominant species accounting for 83% of the total cell density. Nutrient enrichment experiments showed that algae could grow rapidly within 3 days with average specific growth rates (μ) of 0.36–0.42 d−1. The addition of N and P furtherly promoted the algal growth, and μ values of the treatments with P addition were the highest at 0.67–0.83 d−1. These results indicated that even if the WRT was reduced to 3 days, the risk of the occurrence of algal blooms still exists, and this undesirable trend would be enhanced by the short-term external nutrient input. Our findings indicated that the hydrodynamic control measures may not be entirely successful in protecting the drinking water source from algal blooms, especially when its influent has already been under eutrophication. • Shortening WRT may not successfully protect the lakes from algal blooms. • Algal biomass increased across the flow direction of the reservoir with a 3-day WRT. • High N in the influent promoted the succession of dominant species to cyanobacteria. • External nutrient input promotes algal growth and enhances the risk of algal blooms. [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]

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C‐terminal synapsin Ⅰ (83–705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild‐type mice results in the production of the synapsin Ⅰ (83–705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP‐generated synapsin Ⅰ (83–705) fragment in the hippocampus of tau P301S transgenic mice and wild‐type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background: The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. Methods: We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. Results: We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. Conclusions: These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM. [ABSTRACT FROM AUTHOR]

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM. • IAPP interacts with α-synuclein and accelerates its aggregation. • IAPP enhances the seeding activity and neurotoxicity of α-synuclein fibrils. • Administration of IAPP promotes α-synuclein pathology and PD-like phenotypes. [ABSTRACT FROM AUTHOR]

• AEP age-dependently cleaves γ-adducin at N357 in AD. • The AEP-generated γ-adducin (1-357) fragment translocates into nucleus and inhibits neurites growth. • γ-adducin (1-357) fragment induces neurites deficits and synaptic dysfunction by downregulating Rac2. • γ-adducin (1-357) fragment promotes AD-like pathology and cognitive impairments in vivo. Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway. Synaptic dysfunction impairs dopamine turnover and contributes to the degeneration of dopaminergic neurons. However, the molecular mechanisms underlying synaptic dysfunction and dopaminergic neuronal vulnerability in PD are not clear. Here, we report that synaptojanin 1 (SYNJ1), a polyphosphoinositide phosphatase concentrated at nerve terminals, is a substrate of a cysteine proteinase, asparagine endopeptidase (AEP). SYNJ1 is cleaved by the cysteine proteinase AEP at N599 in the brains of PD patients. AEP-mediated cleavage of SYNJ1 disrupts neuronal phosphoinositide homeostasis and causes synaptic dysfunction. Overexpression of the AEP-generated fragments of SYNJ1 triggers synaptic dysfunction and the degeneration of dopaminergic neurons, inducing motor defects in the α-synuclein transgenic mice. Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. Our results demonstrate that the fragmentation of SYNJ1 by AEP mediates synaptic dysfunction and dopaminergic neuronal degeneration in PD. • Synaptojanin 1 is a substrate of asparagine endopeptidase. • Asparagine endopeptidase cleaves synaptojanin 1 at N599 in the brains of patients with Parkinson's disease. • AEP-derived SYNJ1 fragments induce synaptic dysfunction and neuronal degeneration. • Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. [ABSTRACT FROM AUTHOR]