ß-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer's disease.

Introduction: The study of the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. Methods: The humanized APPNL-G-F knock-in mouse line was crossed to the PS19 MAPTP301S, over-expression mouse line to create the dual APPNL-G-F/PS19 MAPTP301S line. The resulting pathologies were characterized by immunochemical methods and PCR. Results: We now report on a double transgenic APPNL-G-F/PS19 MAPTP301S mouse that at 6 months of age exhibits robust A plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A accumulation. Interestingly, study of immunofluorescence in cleared brains indicates that microglial inflammation was generally stronger in the hippocampus, dentate gyrus and entorhinal cortex, which are regions with predominant MAPT pathology. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. m6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Discussion: Our understanding of the pathophysiology of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. The APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.

Association of dietary carbohydrate and fiber ratio with postmenopausal bone mineral density and prevalence of osteoporosis: A cross-sectional study.

BACKGROUND: This study aimed to investigate the associations of carbohydrate to dietary fiber ratio with bone mineral density (BMD) and the prevalence of osteoporosis in postmenopausal women. METHODS: This cross-sectional study retrieved the data of 2829 postmenopausal women from the National Health and Nutrition Examination Survey (NHANES) database. Weighted univariable logistic regression models were used to investigate the correlations of carbohydrate, dietary fiber, or carbohydrate to fiber ratio with osteoporosis. RESULTS: Higher dietary fiber intake was correlated with decreased odds ratio of osteoporosis [odds ratio(OR) = 0.96, 95% confidence interval (CI): 0.93 to 0.99]. The odds ratio of osteoporosis in postmenopausal women was elevated as the increase of carbohydrate to fiber ratio (OR = 1.80, 95%CI: 1.10 to 2.96). Carbohydrate to fiber ratio >17.09 was related to increased odds ratio of osteoporosis (OR = 1.63, 95%CI: 1.04 to 2.56). Compared to the carbohydrate to fiber ratio ≤11.59 group, carbohydrate to fiber ratio >17.09 was associated with decreased total femur BMD (ß = -0.015, 95%CI: -0.028 to -0.001) and femur neck BMD (ß = -0.020, 95%CI: -0.033 to -0.006) in postmenopausal women. The femur neck BMD in postmenopausal women was decreased with the increase of carbohydrate to fiber ratio (ß = -0.015, 95%CI: -0.028 to -0.001). CONCLUSION: In postmenopausal women, a high carbohydrate/fiber ratio >17.09 is associated with an increased risk of osteoporosis and lower hip BMD and high fiber intake is associated with less osteoporosis and higher hip BMD.

Proximity labeling reveals dynamic changes in the SQSTM1 protein network.

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and of the relationship of the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

High familiar faces have both eye recognition and holistic processing advantages.

People recognize familiar faces better than unfamiliar faces. However, it remains unknown whether familiarity affects part-based and/or holistic processing. Wang et al., Frontiers in Psychology, 6, 559 (2015), Vision Research, 157, 89-96 (2019) found both enhanced part-based and holistic processing in eye relative to mouth regions (i.e., in a region-selective manner) for own-race and own-species faces, i.e., faces with more experience. Here, we examined the role of face familiarity in eyes (part-based, region-selective) and holistic processing. Face familiarity was tested at three levels: high-familiar (faces of students from the same department and the same class who attended almost all courses together), low-familiar (faces of students from the same department but different classes who attended some courses together), and unfamiliar (faces of schoolmates from different departments who seldom attended the same courses). Using the old/new task in Experiment 1, we found that participants recognized eyes of high-familiar faces better than low-familiar and unfamiliar ones, while similar performance was observed for mouths, indicating a region-selective, eyes familiarity effect. Using the "Perceptual field" paradigm in Experiment 2, we observed a stronger inversion effect for high-familiar faces, a weaker inversion effect for low-familiar faces, but a non-significant inversion effect for unfamiliar faces, indicating that face familiarity plays a role in holistic processing. Taken together, our results suggest that familiarity, like other experience-based variables (e.g., race and species), can improve both eye processing and holistic processing.

Malignant germ cell tumor of fallopian tube with rhabdomyosarcoma: a case report and literature review.

BACKGROUND: Mixed germ cell tumors originating from the fallopian tubes are rarely reported, and high-grade rhabdomyosarcoma with differentiated components is even less common. The non-specific clinical manifestations of this tumor are prone to misdiagnosis, and there is still controversy over the treatment plan for this rare differentiated type, and there are limited reports on the prognosis of related diseases. CASE PRESENTATION: Here, we report a 34-year-old woman who presented to our hospital with abdominal pain for two weeks and aggravated for two days. After completing relevant examinations, she underwent transabdominal resection of large tubal masses on the left side of the tube + pelvic lymph node dissection + abdominal paraaortic lymph node dissection + right ovarian cyst excision + greater omentectomy + multipoint peritoneal biopsy. hematoxylin-eosin (H&E) and immunohistochemical (IHC) staining were performed on the surgically resected specimens to further determine the type and nature of the tumor, and 3 cycles of Bleomycin + Etoposide + Cisplatonum (BEP) chemotherapy and 1 cycle of EP(Etoposide + Cisplatonum) chemotherapy were given after surgery. CONCLUSION: Up to now, regular follow-up of the patient's tumor markers and imaging showed no abnormalities, the general condition is good, and the tumor free survival time has reached 24 months.

Accumulation of m6A exhibits stronger correlation with MAPT than ß-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease.

The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular ß-amyloid (Aß) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL-G-F MAPTP301S mouse that at 6 months of age exhibits robust Aß plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aß pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aß accumulation. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.

Accumulation of m6A exhibits stronger correlation with MAPT than ß-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease.

The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular ß-amyloid (Aß) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL-G-F MAPTP301S mouse that at 6 months of age exhibits robust Aß plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aß pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aß accumulation. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.

Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.

Alzheimer's disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.

Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model.

The use of iPSC derived brain organoid models to study neurodegenerative disease has been hampered by a lack of systems that accurately and expeditiously recapitulate pathogenesis in the context of neuron-glial interactions. Here we report development of a system, termed AstTau, which propagates toxic human tau oligomers in iPSC derived neuron-astrocyte assembloids. The AstTau system develops much of the neuronal and astrocytic pathology observed in tauopathies including misfolded, phosphorylated, oligomeric, and fibrillar tau, strong neurodegeneration, and reactive astrogliosis. Single cell transcriptomic profiling combined with immunochemistry characterizes a model system that can more closely recapitulate late-stage changes in adult neurodegeneration. The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 is used to address the putative dysfunctional HSP chaperone system and produces a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.

A binary carbon@silica@carbon hydrophobic nanoreactor for highly efficient selective oxidation of aromatic alkanes.

Nanoreactors with a delimited void space and a large number of mesoporous structures have attracted great attention as potential heterogeneous catalysts. In this work, a cobalt and nitrogen co-doped binary carbon@silica@carbon hydrophobic nanoreactor was synthesized by an in situ synthesis method. Cobalt porphyrin was used as an active component to construct Co-Nx sites, and the purpose of the double carbon layer coating was to enhance the hydrophobicity of the surface of the nanoreactor. The optimal nanoreactor could achieve 96.9% ethylbenzene conversion and 99.1% acetophenone selectivity and showed outstanding universality to many other aromatic alkanes. The superior performance was mainly due to the presence of double carbon layers and the high content of Co-Nx sites. The double hydrophobic carbon layer coating could not only promote the adsorption of organic molecules, but also implant Co-Nx active sites on both the inner and outer surfaces of the nanoreactor. This work proposed a meaningful strategy to obtain a highly efficient nanoreactor for C-H bond oxidation.