I2-Imidazoline Ligand CR4056 Improves Memory,Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.     

CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.     

Melatonin and the Brain–Heart Crosstalk in Neurocritically Ill Patients—From Molecular Action to Clinical Practice

Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain–heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.     

Regulation and Release of Vasoactive Endoglin by Brain Endothelium in Response to Hypoxia/Reoxygenation in Stroke

In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury.     

基于LSDANet的手机芯片屏蔽壳表面缺陷检测方法

为了解决手机芯片屏蔽壳表面白印缺陷微小、尺度各异等因素影响检测快速性和准确性的问题,本文提出一种基于长短连接通路和双注意力网络(long short link and double attention network, LSDANet)的手机芯片屏蔽壳表面缺陷检测方法。首先,通过构建基于编码和解码的语义分割模型和利用长短距离连接通路,提高网络模型对尺度各异缺陷的特征提取能力。其次,分别设计基于通道和空间的注意力机制,增大5—10 pixel尺寸的白印缺陷在空间和通道上的特征权重。最后,融合双注意力机制和长短距离连接通路分割模型,构建LSDANet缺陷检测网络,应用于手机芯片屏蔽壳表面缺陷检测。实验数据表明,LSDANet网络能够达到96.21%的平均像素精度、66.13%的平均交并比和39.03的每秒检测帧数,相比多种语义分割算法均具有更高的检测精度和速度。     

基于多尺度一致性与注意力机制的视网膜血管分割网络

针对现有的视网膜血管分割方法存在对微血管和毛细血管的分割能力不足,导致血管断连和末端血管漏分,造成视网膜血管分割性能不佳的问题,本文提出一种基于多尺度一致性与注意力机制的视网膜血管分割网络(multi-scale consistency and attention mechanism U-Net, MCAU-Net)。首先,该网络在瓶颈特征层嵌入注意力细化模块(attention refinement module, ARM),能有效细化瓶颈层冗余的特征,抑制背景等无关像素的权值。其次,将上下文特征融合模块(context fusion module, CFM)与传统的跳跃连接相结合,以此补充在特征提取过程中逐渐丢失的信息,加强网络对微血管和毛细血管的构建能力。最后,基于网络的多尺度输出设计了一种多尺度一致性的训练方式,以增强网络对不同尺度特征的敏感性。在DRIVE和CHASE＿DB1公开数据集上进行的对比实验表明本文网络具有良好的分割性能。     

一种新型的无人机牧草分割网络—LMS-DeeplabV3+

目前草原环境复杂、牧草分散且与背景颜色差异小,无法实现高效精准的分割,因此本文提出了一种新型的轻量化多尺度DeeplabV3+网络(lightweight and multi-scale DeeplabV3+network, LMS-DeeplabV3+)。该网络以DeeplabV3+为基础网络,首先选用轻量级的MobilenetV2作为骨干网络用于初步特征提取,并为了适应牧草分割任务做了网络配置上的调整;其次在加强特征提取模块和解码模块中均使用深度可分离卷积代替普通卷积以轻量化网络;此外利用密集空洞空间金字塔池化(dense atrous spatial pyramid pooling, DASPP)模块捕获更大的感受野,加强各特征之间的交互;又引入卷积注意力机制(convolutional block attention module, CBAM)重分配权重加强特征提取。实验证明,提出的新网络与原始网络相比平均交并比(mean intersection over union,mIOU)提升了8.06个百分点、平均像素精度(mean pixel accuracy,mPA)提升了6.7...     

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.     

Single-Circulating Tumor Cell Whole Genome Amplification to Unravel Cancer Heterogeneity and Actionable Biomarkers

The field of single-cell analysis has advanced rapidly in the last decade and is providing new insights into the characterization of intercellular genetic heterogeneity and complexity, especially in human cancer. In this regard, analyzing single circulating tumor cells (CTCs) is becoming particularly attractive due to the easy access to CTCs from simple blood samples called “liquid biopsies”. Analysis of multiple single CTCs has the potential to allow the identification and characterization of cancer heterogeneity to guide best therapy and predict therapeutic response. However, single-CTC analysis is restricted by the low amounts of DNA in a single cell genome. Whole genome amplification (WGA) techniques have emerged as a key step, enabling single-cell downstream molecular analysis. Here, we provide an overview of recent advances in WGA and their applications in the genetic analysis of single CTCs, along with prospective views towards clinical applications. First, we focus on the technical challenges of isolating and recovering single CTCs and then explore different WGA methodologies and recent developments which have been utilized to amplify single cell genomes for further downstream analysis. Lastly, we list a portfolio of CTC studies which employ WGA and single-cell analysis for genetic heterogeneity and biomarker detection.     

基于半监督学习的眉毛图像分割方法

眉毛图像的分割,由于受到毛发、姿势及个体差异的影响,是一个非常困难的问题。提出了一种利用半监督学习技术进行彩色眉毛图像分割的方法,首先通过手工在眉毛图像上简单画上几条线标注部分眉毛点和非眉毛点,然后利用半监督学习技术完成眉毛图像分割并从中提取纯眉毛图像,最后通过实验说明该方法具有非常好的分割效果,可用于眉毛识别的前期预处理。