J. Neurochem. (2012) 120 (Suppl. 1), 9–21.
β‐Amyloid precursor protein (APP) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). APP undergoes post‐translational ...proteolysis/processing to generate the hydrophobic β‐amyloid (Aβ) peptides. Deposition of Aβ in the brain, forming oligomeric Aβ and plaques, is identified as one of the key pathological hallmarks of AD. The processing of APP to generate Aβ is executed by β‐ and γ‐secretase and is highly regulated. Aβ toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo. Aside from Aβ, proteolytic cleavages of APP can also give rise to the APP intracellular domain, reportedly involved in multiple types of cellular events such as gene transcription and apoptotic cell death. In addition to amyloidogenic processing, APP can also be cleaved by α‐secretase to form a soluble or secreted APP ectodomain (sAPP‐α) that has been shown to be mostly neuro‐protective. In this review, we describe the mechanisms involved in APP metabolism and the likely functions of its various proteolytic products to give a better understanding of the patho/physiological functions of APP.
Asymmetric one‐carbon homologation or ring expansion of ketones with formal insertion of carbene intermediate, is a challenging but useful strategy to construct a complex skeleton. Sc(III) and chiral ...ligands have been employed in this regard. However, due to flexible conformations and a variety of stereo models, the origin of stereochemistry remains ambiguous. Density functional theory (DFT) calculations were carried out to explore the interactions that control the stereoselectivity of a Sc(III)‐catalyzed asymmetric homologation. The trans influence of counterions was found to affect the coordination mode of ketone to Sc(III), and consequently affect the stereoselectivity.
DFT study of Sc(III)‐catalyzed asymmetric homologation of ketones with diazo compounds revealed a new coordination mode of substrates which was rationalized by the trans influence. The origin of stereo‐selectivity was explored based on the coordination mode. A promising new strategy to adjust stereo‐selectivity by trans influence was proposed.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the ...cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and
-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
Aberrant glucose metabolism and immune evasion are recognized as two hallmarks of cancer, which contribute to poor treatment efficiency and tumor progression. Herein, a novel material system ...consisting of a glucose and TEMPO (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl) at the distal ends of PEO‐b‐PLLA block copolymer (glucose‐PEO‐b‐PLLA‐TEMPO), is designed to encapsulate clinical therapeutics CUDC101 and photosensitizer IR780. The specific core–shell rod structure formed by the designed copolymer renders TEMPO radicals excellent stability against reduction‐induced magnetic resonance imaging (MRI) silence. Tumor‐targeting moiety endowed by glucose provides the radical copolymer outstanding multimodal imaging capabilities, including MRI, photoacoustic imaging, and fluorescence imaging. Efficient delivery of CUDC101 and IR780 is achieved to synergize the antitumor immune activation through IR780‐mediated photodynamic therapy (PDT) and CUDC101‐triggered CD47 inhibition, showing M1 phenotype polarization of tumor‐associated macrophages (TAMs). More intriguingly, this study demonstrates PDT‐stimulated p53 can also re‐educate TAMs, providing a combined strategy of using dual tumor microenvironment remodeling to achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.
This study presents new insights on CUDC101 in the reprogramming of tumor‐associated macrophages toward antitumor M1 phenotype by CD47 inhibition with a glucose‐contained magnetic resonance imaging‐capable supramolecular rod‐like micelle, and phototriggered p53 by codelivery of IR780 can achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.
Neuronal hyperactivity induced by β‐amyloid (Aβ) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying ...mechanisms are still unclear. Here, we revealed that Aβ increased the expression level of synaptic adhesion molecule protocadherin‐γC5 (Pcdh‐γC5) in a Ca2+‐dependent manner, associated with aberrant elevation of synapses in both Aβ‐treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh‐γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh‐γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh‐γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh‐γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh‐γC5 in mediating Aβ‐induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.
We propose the following mechanism in Alzheimer's disease pathogenesis: β‐Amyloid (Aβ) triggers Ca2+ influx and enhanced synaptic adhesion molecule protocadherin‐γC5 (Pcdh‐γC5) expression in a Ca2+‐dependent manner. The cleaved carboxy terminal fragment (CTF) of Pcdh‐γC5 enters the nucleus, further promoting its transcription and various synaptic proteins. Sustained neuronal hyperactivity will eventually induce vesicle depletion and synaptic dysfunction in Alzheimer's disease.
Disclosed here is the first geminal (gem‐) hydroborative cyclization of enynes. Different from known hydroborative cyclizations, this process adds hydrogen and boron to the same position, leading to ...a new reaction mode. With Cp*RuCl4 as catalyst, a range of gem‐hydroborated bicyclic products bearing a cyclopropane unit could be rapidly assembled from simple enyne substrates. Control experiments and density functional theory (DFT) calculations provided important insights into the reaction mechanism. Notably, two major competing pathways may operate with substrate‐dependence. 1,6‐Enynes favor initial oxidative cyclometalation to form a ruthenacyclopentene intermediate prior to engaging hydroborane, while other enynes (e.g., 1,7‐enynes) that lack strong propensity toward cyclization prefer initial alkyne gem‐(H,B)‐addition to form an α‐boryl ruthenium carbene followed by intramolecular olefin cyclopropanation. This process also represents the first ruthenium‐catalyzed enyne hydroborative cyclization.
Different from the previously known hydroborative cyclizations that add hydrogen and boron to opposite sides of an enyne, the proper choice of a ruthenium catalyst alters this propensity to a new addition mode, geminal hydroborative cyclopropanation. Two possible mechanisms are operative, which are substrate‐dependent based on DFT studies.
To conquer the bottleneck of sluggish kinetics in cathodic oxygen reduction reaction (ORR) of metal‐air batteries, catalysts with dual‐active centers have stood out. Here, a “pre‐division metal ...clusters” strategy is firstly conceived to fabricate a N,S‐dual doped honeycomb‐like carbon matrix inlaid with CoN4 sites and wrapped Co2P nanoclusters as dual‐active centers (Co2P/CoN4@NSC‐500). A crystalline {CoII2} coordination cluster divided by periphery second organic layers is well‐designed to realize delocalized dispersion before calcination. The optimal Co2P/CoN4@NSC‐500 executes excellent 4e− ORR activity surpassing the benchmark Pt/C. Theoretical calculation results reveal that the CoN4 sites and Co2P nanoclusters can synergistically quicken the formation of *OOH on Co sites. The rechargeable Zn‐air battery (ZAB) assembled by Co2P/CoN4@NSC‐500 delivers ultralong cycling stability over 1742 hours (3484 cycles) under 5 mA cm−2 and can light up a 2.4 V LED bulb for ≈264 hours, evidencing the promising practical application potentials in portable devices.
A “pre‐division metal clusters” strategy is first conceived to fabricate dual‐active center catalysts (Co2P/CoN4@NSC‐500) with dispersed CoN4 and Co2P sites. The optimal catalyst executes superior ORR activity and was applied in ultralong Zn‐air batteries surpassing the benchmark 20 % Pt/C. Theoretical calculations demonstrate that the dual‐active sites synergistically quicken the formation of the *OOH intermediate, greatly boosting the performance.
Abstract
Maternal mRNA clearance is an essential process that occurs during maternal-to-zygotic transition (MZT). However, the dynamics, functional importance, and pathological relevance of maternal ...mRNA decay in human preimplantation embryos have not yet been analyzed. Here we report the zygotic genome activation (ZGA)-dependent and -independent maternal mRNA clearance processes during human MZT and demonstrate that subgroups of human maternal transcripts are sequentially removed by maternal (M)- and zygotic (Z)-decay pathways before and after ZGA. Key factors regulating M-decay and Z-decay pathways in mouse have similar expression pattern during human MZT, suggesting that YAP1-TEAD4 transcription activators, TUT4/7-mediated mRNA 3ʹ-oligouridylation, and BTG4/CCR4-NOT-induced mRNA deadenylation may also be involved in the regulation of human maternal mRNA stability. Decreased expression of these factors and abnormal accumulation of maternal transcripts are observed in the development-arrested embryos of patients who seek assisted reproduction. Defects of M-decay and Z-decay are detected with high incidence in embryos that are arrested at the zygote and 8-cell stages, respectively. In addition, M-decay is not found to be affected by maternal
TUBB8
mutations, although these mutations cause meiotic cell division defects and zygotic arrest, which indicates that mRNA decay is regulated independent of meiotic spindle assembly. Considering the correlations between maternal mRNA decay defects and early developmental arrest of in vitro fertilized human embryos, M-decay and Z-decay pathway activities may contribute to the developmental potential of human preimplantation embryos.
Background
Computed tomography (CT) is essential for pulmonary nodule detection in diagnosing lung cancer. As deep learning algorithms have recently been regarded as a promising technique in medical ...fields, we attempt to integrate a well‐trained deep learning algorithm to detect and classify pulmonary nodules derived from clinical CT images.
Materials and Methods
Open‐source data sets and multicenter data sets have been used in this study. A three‐dimensional convolutional neural network (CNN) was designed to detect pulmonary nodules and classify them into malignant or benign diseases based on pathologically and laboratory proven results.
Results
The sensitivity and specificity of this well‐trained model were found to be 84.4% (95% confidence interval CI, 80.5%–88.3%) and 83.0% (95% CI, 79.5%–86.5%), respectively. Subgroup analysis of smaller nodules (<10 mm) have demonstrated remarkable sensitivity and specificity, similar to that of larger nodules (10–30 mm). Additional model validation was implemented by comparing manual assessments done by different ranks of doctors with those performed by three‐dimensional CNN. The results show that the performance of the CNN model was superior to manual assessment.
Conclusion
Under the companion diagnostics, the three‐dimensional CNN with a deep learning algorithm may assist radiologists in the future by providing accurate and timely information for diagnosing pulmonary nodules in regular clinical practices.
Implications for Practice
The three‐dimensional convolutional neural network described in this article demonstrated both high sensitivity and high specificity in classifying pulmonary nodules regardless of diameters as well as superiority compared with manual assessment. Although it still warrants further improvement and validation in larger screening cohorts, its clinical application could definitely facilitate and assist doctors in clinical practice.
摘要
背景。在肺癌的诊断中，计算机断层扫描 (CT) 对于肺结节的检测必不可少。近几年，随着医学领域逐渐认识到深度学习算法这种技术的价值，本研究试图集成一种训练有素的深度学习算法，对临床 CT 图像中的肺结节进行检测和分类。
材料和方法。本研究使用了开源数据集和多中心数据集。本文设计了一种三维卷积神经网络 (CNN) 来检测肺结节，然后根据病理和实验室证实的结果，判断为恶性或良性结节。
结果。这种训练有素的模型敏感性和特异性分别为 84.4% 95% 可信区间 (CI)， 80.5%‐88.3%和83.0%(95% CI，79.5%‐86.5%)。小结节 (< 10mm) 亚组分析显示的敏感性和特异性显著，与大结节 (10‐30mm) 相似。对比不同级别医生的人工评估结果与三维 CNN 的评估结果，进行了额外的模型验证。结果表明，CNN 模型的表现优于人工评估。
结论。通过伴随诊断可知，加入深度学习算法的三维 CNN 能够提供准确、及时的信息，有助于放射科医生在常规临床实践中的肺结节诊断工作。
实践意义:在对各种直径的肺结节分类中，本文所述的三维卷积神经网络具有较高的敏感性和特异性，与人工评估结果相比具有优越性。虽然仍需在更大的筛选队列中进行进一步改进和验证，但可以肯定的是，临床应用三维卷积神经网络可以促进和协助医生的临床实践工作。
Interest in deep convolutional neural networks (CNN) is growing because of demonstrated accuracy with less manual intervention in computer vision tasks. This article describes efforts to use a pre‐trained CNN model integrating with multi‐centers datasets for detection and classification of pulmonary nodules.
Objectives
This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its ...prognostic value.
Methods
For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients.
Results
The radiomics signature comprised eight LN-status–related features and showed significant association with LN metastasis in both cohorts (
p
< 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both
p
< 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival.
Conclusions
Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making.
Key Points
• The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup.
• Prognosis of high-risk patients remains dismal after curative-intent resection.
• The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.
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