Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases

The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies.     

UNC-10在致密核心囊泡分泌过程中的作用

Rim是囊泡分泌活性区中的重要组成蛋白,它与细胞分泌和突触可塑性相关．在秀丽隐感线虫中只存在一种编码Rim的基因即unc-10．我们的研究发现,在线虫中Rim的基因突变unc-10(md1117)会导致致密核心囊泡的分泌缺陷．在活体中,unc-10突变虫系的神经多肽分泌显著下降．此外,在主要分泌致密核心囊泡的ALA神经元内,钙光解释放促发的快相分泌也比野生型减少．运用全内反射荧光显微成像技术,我们观察在unc-10缺失的情况下ALA 神经元中致密核心囊泡的锚定过程,结果显示在细胞膜附近停留的囊泡数目减少,表明囊泡锚定受到阻碍．上述试验结果表明,UNC-10能够影响致密核心囊泡的分泌过程,其机制可能是影响了囊泡的锚定过程．     

ESYT-2 在致密核心囊泡分泌中起到的作用

目的:研究秀丽隐杆线虫(简称线虫)中一种扩展的Synaptotagmin同源物ESYT-2在致密核心囊泡分泌过程中起到的作用。方法:以线虫为研究对象,运用线虫腔胞吸收ANF-GFP的基本原理来确定ESYT-2与分泌相关,之后又进一步使用全内反射荧光显微镜技术(TIRFM)来研究ESYT-2对致密核心囊泡的具体调控。结果:①ESYT-2功能缺失影响线虫神经细胞致密核心囊泡分泌。②ESYT-2影响致密核心囊泡分泌的栓系过程。结论:ESYT-2调控了致密核心囊泡的分泌过程。     

线虫全基因组RNAi筛选确定CAB-1为特异性调节致密核心囊泡分泌的因子

内分泌细胞和神经细胞通过释放激素和神经肽类物质来响应外界刺激,而这些物质的分泌,都是通过致密核心囊泡(dense core vesicle,DCV)来实现的.但是,现阶段关于DCV的生成、转运、释放的机制很大程度上是不清楚的.在本研究中,我们将线虫的排便行为和肠道分泌联系起来,并以此表型进行全基因组RNAi筛选,寻找调节DCV的新基因.我们成功筛选到了一些在肠道调节DCV生成或释放的基因.其中,CAB-1被确认为特异性调节DCV分泌的重要因子.在肠道中,cab-1突变会降低肠道DCV内容物的分泌,而在神经系统中,CAB-1的缺失也会导致DCV的标识物堆积在突触前,而突触囊泡(synaptic vesicle,SV)不受影响.     

Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells

The control of insulin release from pancreatic beta cells helps ensure proper blood glucose level, which is critical for human health. Protein kinase C has been shown to be one key control mechanism for this process. After glucose stimulation, calcium influx into beta cells triggers exocytosis of insulin-containing dense-core granules and activates protein kinase C via calcium-dependent phospholipase C-mediated generation of diacylglycerol. Activated protein kinase C potentiates insulin release by enhancing the calcium sensitivity of exocytosis, likely by affecting two main pathways that could be linked: (1) the reorganization of the cortical actin network, and (2) the direct phosphorylation of critical exocytotic proteins such as munc18, SNAP25, and synaptotagmin. Here, we review what is currently known about the molecular mechanisms of protein kinase C action on each of these pathways and how these effects relate to the control of insulin release by exocytosis. We identify remaining challenges in the field and suggest how these challenges might be addressed to advance our understanding of the regulation of insulin release in health and disease.     

Insect Antiviral Innate Immunity: Pathways,Effectors, and Connections

Insects are infected by a wide array of viruses some of which are insect restricted and pathogenic, and some of which are transmitted by biting insects to vertebrates. The medical and economic importance of these viruses heightens the need to understand the interaction between the infecting pathogen and the insect immune system in order to develop transmission interventions. The interaction of the virus with the insect host innate immune system plays a critical role in the outcome of infection. The major mechanism of antiviral defense is the small, interfering RNA pathway that responds through the detection of virus-derived double-stranded RNA to suppress virus replication. However, other innate antimicrobial pathways such as Imd, Toll, and Jak-STAT and the autophagy pathway have also been shown to play important roles in antiviral immunity. In this review, we provide an overview of the current understanding of the main insect antiviral pathways and examine recent findings that further our understanding of the roles of these pathways in facilitating a systemic and specific response to infecting viruses.     

Frequency Distribution of F-Latencies (DFL) has Physiological Significance and Gives Distribution of Conduction Velocity (DCV) of Motor Nerve Fibres With Implications for Diagnosis

On electrical stimulation of a peripheral motor nerve, a delayed and reduced F-response is obtained, which is known to occur due to random backfiring of a few percent of the motor nerve fibres at the spinal end after antidromic conduction. F-latencies obtained from multiple stimulations vary in latency, size and shape because of this randomness. We hypothesised that, being a random process, recruitment of fibres for F-response would depend on the distribution of conduction velocity (DCV) for motor nerve fibres directly, and therefore, a frequency distribution of F-latencies (DFL) from such multiple F-responses would be an approximate mirror image of DCV, latency being inversely proportional to velocity. First, obtaining DFL from many human subjects, we have shown that this is a reproducible parameter for a nerve trunk of a subject, and hence reveals a new physiological phenomenon. DFL has a single peaked distribution, which is also expected for the DCV of a normal healthy motor nerve. To validate its hypothesised relationship to DCV further, DFLs were obtained from both median nerves of patients with unilateral carpal tunnel syndrome (CTS). The patterns of DFL from both sides remained almost the same except for a delay shift equal to that in between the two M-responses, which lends support to this hypothesis. DFL, and DCV as its suggested mirror image, appear to change systematically with certain known disorders such as cervical spondylosis, even at a subclinical stage, which needs further study. This also indicates that DFL may become a new and improved investigative diagnostic tool in neurophysiology.     

Infection avoidance behavior: Viral exposure reduces the motivation to forage in female Drosophila melanogaster

Infection avoidance behaviors are the first line of defense against pathogenic encounters. Behavioral plasticity in response to internal or external cues of infection can therefore generate potentially significant heterogeneity in infection. We tested whether Drosophila melanogaster exhibits infection avoidance behavior, and whether this behavior is modified by prior exposure to Drosophila C Virus (DCV) and by the risk of DCV encounter. We examined 2 measures of infection avoidance: (1) the motivation to seek out food sources in the presence of an infection risk and (2) the preference to land on a clean food source over a potentially infectious source. While we found no evidence for preference of clean food sources over potentially infectious ones, previously exposed female flies showed lower motivation to pick a food source when presented with a risk of encountering DCV. We discuss the relevance of behavioral plasticity during foraging for host fitness and pathogen spread.     

Frequency Domain Analysis to Identify Neurological Disorders from Evoked EMG Responses

Evoked EMG M-responses obtained from the thenar muscle in the palm by electrical stimulation of the median nerve demonstrate a well-established smooth bipolar shape for normal healthy subjects. Kinks in this curve are observed in certain neurological disorders and preliminary work suggests their relationship to cervical spondylosis. The present work was taken up to develop an objective method for the identification of such neurological disorders for automated diagnosis by analysing the M-responses. A Fourier transform was performed using MATLAB, and features in the frequency domain were studied to distinguish healthy and smooth M-responses from ones with kinks. The features included some basic parameters like peak amplitude, peak frequency, frequency bandwidths, and areas in specified frequency segments. Ratio and deviation parameters from the above basic parameters were also studied to make 39 parameters in all. Out of these 10 came out as ‘highly significant’, 17 as ‘significant’ and the rest as insignificant, in statistical t-tests. A weighted combination of the significant parameters may allow identification of kinks with confidence.