Abstract:Huntington’s disease (HD) is an autosomal dominant hereditary neurodegenerative disorder, caused by mutation of Htt gene which encoding huntingtin (Htt). Expanded Htt proteins form aggregates accumulated in cells and result in progressive neuronal degeneration and dysfunction. There are many hypothesis on the pathogenesis of HD, such as oxidative stress and mitochondrial dysfunction. Report on Nature in 2017 highlights that DNA repair as a shared mechanism in neurodegenerative disorders. More and more evidences indicate that DNA repair mechanisms have been implicated in Huntington’s Disease, mutant Htt triggers different types of DNA lesions and excessive activation of DNA damage response. HD is associated with cellular radiosensitivity and double strand break repair defect, and mutant Htt impact the normal function of ATM(ataxia tetangtectasia mutated) in DNA repair. Moreover, DNA repair proteins also impact the onset age of HD. Targeting ATM can ameliorates mutant Huntingtin toxicity in cells and animal models of HD. ATM has a important role in regulating celluar homeostasis and mitochondria signaling, so the mechanism of targeting ATM is more and more clear. This review introduces recent advances in HD and DNA damage response, opens a new direction for study of pathogenic mechanism and development of therapies.

Abstract:Homeobox (HOX) genes, coding for transcription factors, are located in clusters in chromosomes and are important for defining body segment boundary. HOX genes show specific expression pattern in correspondent body part, and their expressions also represent the location information of an adult cell. HOX genes take important role in cancer initiation and progression. Researches on HOX in leukamia have contituously been concerned, while researches on HOX in solid tumors, including lung cancer, gastrointestinal cancer, breast cancer and prostate cancer gain growing attention recently. It is of great importance to illustrate HOX expression regulation, cellular level function and transcriptional activity regulation for clarifying the role of HOX in cancer.

Abstract:Bcl-2-modifying factor (BMF) is a member of the BH3-only family of proapoptotic proteins. Under physiological conditions, BMF is sequestered to the cytoskeleton by association with dynein light chains 2, which prevents BMF to induce cell apoptosis. Some damage stimuli can release BMF from the cytoskeleton, allowing it to translocate to mitochondria and initiate mitochondrial apoptosis pathway. The proapoptotic activity of BMF is regulated at the transcriptional, translational and posttranslational levels. The upregulated and overexpressed BMF is also located predominantly in mitochondrial membranes that is consistent with its ability to induce cell death. Therefore, BMF is a powerful inducer of apoptosis.

Abstract:It’s difficult for biomacromolecules to permeate the barrier of the stratum corneum. As a novel transdermal drug delivery system, microneedles not only greatly promote the transdermal rate and absorption of biological macromolecules, but also possess several advantages like minimal invasiveness, slight pain and convenience. In this paper, the advances in the application of microneedles loaded with biomacromolecule drugs were reviewed in detail, including the promotion of biomacromolecules by individual microneedle arrays (e.g. solid microneedles, hollow microneedles, coated microneedles and soluble microneedles) and combination of microneedles and other pharmaceutic techniques (such as microparticle delivery system), medical devices and intelligent drug-release system. The combinations between microneedle arrays and other technologies have potential to solve the problems that unable for the single microneedle delivery system. In addition, the current problems encountered of microneedle array technique are summarized, and the prospect of microneedles in the field of macromolecular drug delivery is forecasted.

Abstract:High frequency stimulations (HFS) of electrical pulses with different durations have different effects on the nervous system in brain. A short HFS train with a duration of several seconds can be used to establish epilepsy models in animals via a “kindling” effect. It can also produce changes of synaptic plasticity that may persist. However, a long HFS train with a duration several minutes or longer can be safely applied in deep brain stimulation to treat various brain diseases in clinic. Therefore, we speculate that a sustained HFS could change the neuronal responses induced by a short HFS. To verify this hypothesis, 100 Hz HFS with durations of 5 s and 2 min were applied to the Schaffer collateral of afferent fibers in the hippocampus CA1 region of rats. The response potentials of downstream populations of neurons, i.e., population spikes (PS), evoked by a single test pulse were monitored after the termination of HFS trains. The evoked-PS potentials following the two types of stimulation were compared. The results showed that after-discharge events with epileptiform activity appeared immediately following 5 s short HFS trains. In addition, the changes of amplitude and latency of the evoked-PS suggest an increase of excitability persisting for tens of minutes after the termination of 5 s short HFS. In contrast, silent periods of a few tens of seconds without any neuronal firing appeared immediately following 2 min long HFS trains. Furthermore, the amplitude of evoked-PS by test pulses recovered to the baseline level in a few minutes after the termination of long HFS. Because long HFS trains include short HFS trains, these results indicate that the late stimulation of long trains can change the effects on the downstream neural networks produced by their early phases and eliminate the long-term excitatory effects induced by short trains. These findings are of significance for further revealing HFS mechanisms and for advancing the clinical applications of deep brain stimulation.

Abstract:Enterovirus 71 (EV71) is the main causing agent of hand-foot-mouth disease (HFMD), however, the specific antiviral agents are still not commercially available. In order to find antiviral agents against EV71, a high throughput drug-screening model targeting EV71 3C^pro was established and a small-molecular compound library was screened. The virus EV71-MZ was isolated from an HFMD patient, and identified by PCR. A 3C^pro recognition site was inserted into the middle region of YFP open reading frame to generate the mYFP by insertion mutation. The full length mYFP proteins were observed by fluorescence microscope and the protein level was measured by using microplate reader in Ex(500 nm)/Em(535 nm). Change of the fluorescence value reflected the degree of the inhibition on 3C^pro activity. A small-molecular compound was screened by using the established screening model in the high throughput drug screening system, then the antiviral activity of the active compounds was further evaluated by plaque assay. As a result, mYFP expressed well in 293A cell; the expression of 3C^pro reduced the fluorescence signal remarkably, however, the signal was recovered by adding Rupintrivir, an inhibitor of 3C^pro. These results indicated that the screening model targeting 3C^pro was established successfully. 26 of 26 000 compounds significantly reverted the fluorescence signal of the mYFP in the presence of 3C^pro; noticeably, two of the 26 compounds, i.e. numbering 3 and 8, exhibited strong antiviral activity by plaque assay. All together, 3C-mYFP co-expression system is an optimized and effective screening method for high-throughput screening of anti-EV71 3C^{pro drugs.}

Abstract:The spread of HIV-1 in the world is a serious threat to people’s physical and mental health. Residue mutation of HIV-1 protease seriously weakened the effect of drug treatment. In order to study the effects of mutations D30N, I54M and V82A on the interaction between protease and the inhibitor GRL-0519, we carried out four 30 ns molecular dynamics (MD) simulations combined with the solvated interaction energy (SIE) method to calculate the binding free energies of protease and inhibitor. The results show that polar interactions are unfavorable for the mutated protease bonding to the inhibitor, and slightly favorable for WT, the polar interactions are the main driven force for the drug resistance. The calculated total free energies are consistent with the experimental data. In order to show the contribution of each residue to drug resistance, the van der Walls energies of each residue were calculated by the molecular force field method, the hydrogen bonds between inhibitor and protease were also analyzed. The van der Walls analysis implies that the V82A has smaller influence on the binding model. There are five residues with van der Waals contribution larger than 0.4 kcal/mol for D30N, and six residues for I54M. The hydrogen bond analysis suggests that D30N and I54M lost several hydrogen bonds relative to in WT. The result was in accordance with the SIE results. Our study provides theoretical guidance for the design of new and more potent inhibitors against HIV-1 protease variants.

Abstract:In order to understand the cardiac electrophysiological mechanism more deeply as well as analyze and present complex electrophysiological activities of the heart, in this work we constructed a blending model to reveal the biophysical features of the heart. This model combined the mathematical physiological model of cardiac myocytes with the true cardiac tissue by the proposed energy blending absorption coefficient, which maps the tissue and electrophysiological attribute to the different optic property. The physiological activities of the heart in the three dimensional space are thus presented. The experimental results show that based on the blending model, the whole electrical conduction process in three-dimensional space within the inhomogeneous tissue at different time and the location where the activity starts and ends are clearly explored. Cardiac researchers are thus able to understand and deeply recognize the function mechanism of human cardiac bioelectricity physical system in a visual way, which helps to further speculate on the physiological and pathological responses of the heart.

Abstract:How the brain works is one of the most mysterious yet challenging problems in life sciences. Understanding the molecular and neural basis of cognition and memory is expected to not only aid the exploration of the pathogenesis of neurological and neuropsychiatric disorders but also provide the fundamental principles for brain-inspired intelligence. Various neural technologies are continuously developed to provide tools for resolving this ultimate biological problem. Such technologies include molecular genetic tools (particularly genetically encoded calcium indicators and viral trans-synaptic labeling vectors) that images neural circuit activities and neuro-anatomy. CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system is a powerful molecular genetic tool that has revolutionized various scientific fields, especially genome editing, gene expression control, cellular imaging, and molecular tracing. In this review, we discuss the applications and limitations of CRISPR/Cas9 technology in neuroscience and provide possible directions and strategies for the advancement of CRISPR/Cas9 technology in studying the neural basis of cognition and memory.

Abstract:ATP binding cassette transporter A1 (ABCA1) is a transmembrane protein that regulates intracellular cholesterol efflux and is closely related to the development of atherosclerosis (AS). But its structure and molecular mechanisms are still unclear. Recently an issue published on Cell (2017,169:1228-1239) by researchers from Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, China reported the cryo-EM structure of human ABCA1 and suggested a plausible ‘‘lateral access’’ mechanisms for ABCA1-mediated lipid export.