Abstract:A lack of effective treatments for patients suffered from breast cancer with bone metastasis are caused by limited in vitro models and unsuitable animal models, which leads to 70%~80% mortality rate. Microfluidics enabled bone-on-a-chip could facilitate the resemblance of the biochemical and biophysical microenvironment of native bone tissues, which could readily be incorporated with the occurrence of breast cancer so as to recapture the bone metastasis in a single chip. The microscale chip design could be scaled up with high throughput/content settings so as to uncover the molecular mechanisms existing in bone metastasis of breast cancer and screen effective drugs for it more efficiently. In this review, we first introduce the current mechanistic understanding on bone metastasis of breast cancer and existing drugs for this disease. We then summarized the microfluidic models used for recapturing bone metastasis phenomena. We also presented high throughput designs aiming for more efficient drug discovery and development. Lastly, we discuss the advantages and challenges existing in combining high throughput setting and microfluidic models aiming for effective drug screening targeting bone metastasis of breast cancer. Together, we hope to provide a clue on how effective treatments could be discovered in the future so as to decrease the high mortality rate of bone metastasis of breast cancer.

Abstract:Using light as input signal, optogenetics technology can precisely regulate the physiological functions of cells and has high specificity of time and space, which makes it possible to construct highly dynamic regulatory system. In recent years, with the discovery of novel photosensitive proteins and the innovation of light systems, the efficiency of optogenetics-based light control systems has been significantly improved. The application of light control system in bacteria is becoming more and more extensive. By using the lightcontrol system as an input module and combining it with other biological function modules, the regulation of gene expression, protein activity and bacterial physiological function can be realized. This paper mainly introduces the basic principle of optogenetics and its application in synthetic biology and the regulation of bacterial life activities.

Abstract:Songbird is one of the few animals with complex phonological learning ability except human. The song of a songbird is similar to the production of human language. Using songbirds as models, the comparative physiology study provides important insights into the neural mechanisms that regulate language sequences and language learning and production in humans.The singing of songbirds is regulated by the interrelated singing control nuclei. Dopamine, an important neurotransmitter in the brain, is involved in the regulation of movement, cognition, motivation, reward, addiction and learning in mammals, it has been linked to Parkinson's disease, schizophrenia and Huntington's syndrome in humans. DA is a key substance in the brain that regulates learning and motivation. In songbirds, dopamine and its receptors are found in a large number of singing-related nuclei. In addition, recent studies have shown that dopamine promotes songbird song learning in juvenile stage, song retention in adulthood, and song production in courtship by regulating the singing-related nuclei. Based on the research of our work , this paper reviews the research progress in the regulation of the dopamine system on the singing-related nuclei and singing behavior of songbirds, the potential mechanism of dopamine signal regulating singing behavior of songbirds was proposed.

Abstract:Sensory cortex neurons of non-classical receptive field on the classical receptive field adjustment widely exist in mammals, is considered to be the basic characteristic of the sensory cortex neurons. In primary visual cortex of mammals, there was a larger non-classical receptive filed (nCRF) region beyond the classical receptive field (CRF). Although the region was not directly respond to the visual stimulus, it can modulate cell’s response in classical receptive fields. Understanding the modulatory mechanism of non-classical receptive field in V1 neurons can reveal the basic principles of information processing in mammalian sensory cortical neurons. At present, many studies found that modulatory mechanism of nCRF arises from feed forward, horizontal, and feedback interactions with local recurrent connections through synaptic mechanisms involved in increased inhibition and reduction of recurrent excitability. The modulatory by nCRF can effectively reduce the redundancy of the visual input. In general, surround suppression is generated by multiple connection types. Feedforward and horizontal connections in V1 mainly provide surround suppression from just outside the classical receptive field, and feedback from progressively higher areas provide modulation from progressively more distant surround regions. Moreover, feedback connections from different cortical areas likely modulate V1 responses in a stimulus-specific fashion, which is crucial for the large-scale information processing in the primary visual cortex.

Abstract:Chronic pain is one of the most common clinical symptoms and has been considered as a global healthcare problem. Currently, the underlying mechanisms of the transition from acute to chronic pain, also known as pain chronification, still remain incompletely understood. Neuroimaging studies indicated that the corticolimbic circuitry (prefrontal cortex, amygdala, hippocampus, nucleus accumbens, ventral tegmental area) is preferentially involved in encoding fluctuations of ongoing pain for various chronic pain conditions, suggesting the critical role of this neural circuitry in pain chronification. In this review, we first summarized the emotion, motivation, and memory dysfunctions and their corresponding structural and functional changes of the corticolimbic circuitry in chronic pain patients. Then, we reviewed the longitudinal brain imaging studies on low back pain chronification and highlighted the neuroimaging variables (i. e., the structural and functional properties of the corticolimbic circuitry) that could predict the transition from acute to chronic pain. For example, the functional connectivity between the medial prefrontal cortex and nucleus accumbens/hippocampus, as well as the functional connectivity between the dorsal medial prefrontal cortex and amygdala/nucleus accumbens could predict the development of chronic pain 1 year later. Besides, based on the existing theoretical model of chronic pain, we emphasized the critical role of the reinforcement learning of negative emotions as well as the dysfunctions of reward and stress systemin pain chronification. Finally, we pointed out the limitations of previous studies in this field and suggested future research directions for a better understanding of the neural mechanisms of chronic pain and pain chronification.

Abstract:Noise widely exists in animals and human everyday life, it has negative influence on animals from invertebrates to mammals, and even human beings. High level noise can cause damage to auditory structure and function, decrease auditory neural sensitivity and behavioral acuity, and even lead to noise-induced hearing loss (NIHL). In this review, we summarized influence impacts and classification of NIHL, and possible mechanisms underlying the NIHL. Previous research on NIHL showed that the NIHL was related to postsynaptic terminals swelling, reversible excitotoxicity induced by glutamate and reactive oxygen species (ROS) evoked oxidative stress, cell apoptosis, synaptic ribbons damage and increasing express level of mRNA of guanine nucleotide binding protein alpha stimulating (GNAS) and their upstream lncRNAs Sept7. We further compared the differences in hearing loss among different species, and found that all species exhibited various degree of hearing loss after noise exposure excepting the echolocation bats. The fishes and birds can quickly recover from the hearing damage because their hair cells have the ability to regenerate. Comparing with the rodent which is more susceptive to noise influence, the echolocation cetacean have a small temporary threshold shift (TTS) after high intensity noise exposure, and the specialized inner ear structure is thought to be the possible reason. It is interesting that the echolocation bat do not exhibit TTS even exposed to high intensity noise, which is thought to be an adaption to their living environment, and forward studies on the underlying neurophysiological mechanisms will help us fully understand and solve the NIHL. These conclusions indicated that comparative physiological study on different species can help us deeply reveal the mechanism underlying NIHL, and provide a reference for hearing protection and repairing of noise induced hearing loss.

Abstract:Endometrial cancer(EC) is the most common tumors in women, with the rate of incidence and mortality has been greatly increased recently. With the wide application of targeted therapy in clinic, exploring new targets has been the most critical link in the accurate treatment of endometrial carcinoma. More and more studies have found that the E3 ubiquitin ligase adaptor speckle-type POZ protein (SPOP) plays an important role in the development of EC. In this review, we analysed recent research articles in this field and focused on the current research status of EC and ubiquitin-proteasome system(UPS) , the structure and function of SPOP, factors influencing and regulating SPOP and the mutations and substrates of SPOP in EC. Moreover, we summarized the molecular role of SPOP on repressing EC mostly in three key signal pathways: estrogen receptor-α(ERα) -mediated signaling pathway, bromodomain and extraterminal protein(BET) pathway and zinc finger and BTB domain-containing protein 3(ZBTB3) pathway. We look forward to SPOP as the new molecular targeted therapy for EC.

Abstract:Human brain is a complex system with powerful abilities of signal processing, which determines our cognition, emotion, consciousness, and behavior. As a computational device, our brain needs to continuously consume metabolic energy to realize above functions. Most of brain's energy usage is consumed on information coding by single neurons, and the subcellular processes consuming metabolic energy include generating and propagating action potentials, maintaining rest potentials, and synaptic transmission. A neuron uses sequences of action potentials as a principal carrier to represent and transmit information. Generating and propagating these electrical signals makes a significant contribution to the overall consumption of metabolic energy in the brain. The biophysical properties of voltage-dependent ionic conductances determine the action potential energy consumption. The cell specificity and spatial heterogeneity of biophysics lead to a high variation in the action potential metabolic efficiency, which brings challenges for understanding the principles, causes, and consequences of metabolic cost of information coding by single neurons. In this paper, we first introduce how the subcellular processes involving in neuronal information coding consume metabolic energy. Then, we present an exhaustive review on the main findings of action potential metabolic cost in recent years, and mainly discuss how biophysical properties and spike shape affect the action potential energy efficiency. Finally, we raise several key issues on the metabolic consumption of neuronal information coding that need to be addressed in the future.

Abstract:Based on the powerful secondary metabolism of Streptomyces, they have been used to synthesize many biologically active secondary metabolites, such as antibiotics, anti-tumor drugs and immunosuppressants. Due to the fact that the synthesis of these products is often strictly regulated at multiple levels, therefore, the study of the mechanism of secondary metabolism regulation of Streptomyces can not only deepen our understanding of the metabolic regulation network of Streptomyces, but also provide important reference and guidance for the construction of industrial producing strains from the perspective of metabolism. There are two key types of signal transduction system in Streptomyces: two-component system (TCS) and extracytoplasmic function σ (ECF-σ). Both of them play important regulatory functions in the process of antibiotic biosynthesis. Studies have shown that there are a large number of TCS and ECF-σ coding genes in the genome of Streptomyces coelicolor, a model Streptomyces strain. In our previous studies, we have showed that, under certain conditions, the sigQ-afsQs gene cluster in S. coelicolor is involved in the regulation of the biosynthesis of ACT (actinorhodin), RED (undecylprodigiosin) and CDA (calcium-dependent antibiotic) antibiotics. Based on the early stage research on the regulation function of the TCS system afsQ1/Q2, a detailed study of the upstream regulation mechanism toward afsQ1/Q2 was carried out in this work. Through gene function verification experiments, it was found that the loss of sigQ can significantly down-regulate the expression of the membrane protein gene afsQ4 in the sigQ-afsQs gene cluster, and at the same time complementation afsQ4 can restore the phenotype of the sigQ deletion mutant (?sigQ), which indicates that afsQ4 is the downstream regulatory target of sigQ. Further analysis of in vitro phosphorylation experiments showed that the phosphorylation level of the transmembrane kinase AfsQ2 of TCS was significantly reduced in afsQ4 gene deletion mutant, indicating that sigQ can negatively regulate the TCS afsQ1/Q2 through membrane protein AfsQ4, and finally coordinate antibiotic synthesis.

Abstract:The dynamic balance of excitation and inhibition systems in the cerebral cortex determine the response characteristics of neurons to the stimulation. It has been reported that metformin can induce the postsynaptic clustering of gamma-aminobutyric acid (GABA) receptors and enhance inhibition in the nervous system. Here we explore the regulatory effect of metformin on the balance of the excitatory and the inhibitory system of the primary visual cortex, and its potential to improve visual function in mice. Adult male mice were treated with metformin (metformin group) and normal saline (control group) for 3 weeks of intragastril administration. We found that metformin can significantly increase the production of vesicle GABA transporter (VGAT) and postsynaptic inhibitory receptor-related protein (Gephyrin). Furthermore, it significantly reduced the expression of postsynaptic excitatory receptors GluA1 and GluN1. The data also demonstrated that the multichannel electrode recording shows that Baseline Response and Maximum Response of the primary visual cortex were significantly decreased, while under the treatment of metformin the signal-to-noise ratio, directional and orientation bias were significantly increased. Our finding reveals that metformin could reduce the excitation synapse, enhance the inhibition synapse, and adjust the balance of excitation-inhibition of the primary visual cortex, thus improving information processing ability and enhancing visual function.