Inhibition of kinetic random-distribution in DNA Seesaw gates and biosensors for complete leakage prevention.

DNA nanomaterials have a wide application prospect in biomedical field, among which DNA computers and biosensors based on Seesaw-based DNA circuit is considered to have the most development potential. However, the serious leakage of Seesaw-based DNA circuit prevented its further development and application. Moreover, the existing methods to suppress leakage can't achieve the ideal effect. Interestingly, we found a new source of leakage in Seesaw-based DNA circuit, which we think is the main reason why the previous methods to suppress leakage are not satisfactory. Therefore, based on this discovery, we use DNA triplex to design a new method to suppress the leakage of Seesaw-based DNA circuit. Its ingenious design makes it possible to perfectly suppress the leakage of all sources in Seesaw-based DNA circuit and ensure the normal output of the circuit. Based on this technology, we have constructed basic Seesaw module, AND gate, OR gate, secondary complex circuits and DNA detector. Experimental results show that we can increase the working range of the secondary Seesaw-based DNA circuit by five folds and keep its normal output signal above 90%, and we can improve the LOD of the Seesaw-based DNA detector to 1/11 of the traditional one(1.8pM). More importantly, we successfully developed a detector with adjustable detection range, which can theoretically achieve accurate detection in any concentration range. We believe the established triplex blocking strategy will greatly facilitate the most powerful Seesaw based DNA computers and biosensors, and further promote its application in biological systems.

Discovery of Novel Diphenyl Acrylonitrile Derivatives That Promote Adult Rats' Hippocampal Neurogenesis.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy.

The mechanisms of the transplantation of neural stem cells (NSCs) in the treatment of Alzheimer's disease remain poorly understood. In this study, NSCs were transplanted into the hippocampal CA1 region of the rTg (tau P301L) 4510 mouse model, a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer's disease. The results revealed that NSC transplantation reduced the abnormal aggregation of tau, resulting in significant improvements in the short-term memory of the tauopathy model mice. Compared with wild-type and phosphate-buffered saline (PBS)-treated mice, mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue, particularly those related to the regulation of tau aggregation or misfolding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation, neurogenesis, and other neurobiological processes. Changes in the expression levels of key proteins were verified by western blot assays. These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer's disease treatment. This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology (approval No. SYXK-BIT-school of life science-2017-M03) in 2017.

Optogenetic stimulation of CA3 pyramidal neurons restores synaptic deficits to improve spatial short-term memory in APP/PS1 mice.

The hippocampal CA3 region, that is involved in the encoding and retrieval of spatial memory, is found to be synaptically impaired in the early-onset of Alzheimer's disease (AD). It is reported optogenetic manipulation of DG or CA1 can rescue the memory impairment of APP/PS1 mice, however, how CA3 region contributes to AD-related deficits in cognitive function is still unknown. Our work shows optogenetic stimulation of CA3 pyramidal neurons (PNs) significantly restores the impaired spatial short-term memory of APP/PS1 mice. This enhances the anatomical synaptic density/strength and synaptic plasticity as well as activates astrocytes. Chemogenetic inhibiting the activity of CA3 astrocytes reverses the effect of optogenetic stimulation of CA3 PNs that leads to reduced anatomical synaptic density/strength, decreased synaptic protein and AMPA receptors GluA3/4, thus disrupting the cognitive restoration of APP/PS1 mice. These results reveal the molecular mechanism of optogenetic activation of CA3 PNs on restoration of the spatial short-term memory of APP/PS1 mice and unveil a potential strategy of manipulating CA3 for AD treatment.

Expression of tardigrade disordered proteins impacts the tolerance to biofuels in a model cyanobacterium Synechocystis sp. PCC 6803.

Tardigrades, known colloquially as water bears or moss piglets, are diminutive animals capable of surviving many extreme environments, even been exposed to space in low Earth orbit. Recently termed tardigrade disordered proteins (TDPs) include three families as cytoplasmic-(CAHS), secreted-(SAHS), and mitochondrial-abundant heat soluble (MAHS) proteins. How these tiny animals survive these stresses has remained relatively mysterious. Cyanobacteria cast attention as a "microbial factory" to produce biofuels and high-value-added chemicals due to their ability to photosynthesis and CO2 sequestration. We explored a lot about biofuel stress and related mechanisms in Synechocystis sp. PCC 6803. The previous studies show that CAHS protein heterogenous expression in bacteria, yeast, and human cells increases desiccation tolerance in these hosts. In this study, the expression of three CAHS proteins in cyanobacterium was found to affect the tolerance to biofuels, while the tolerance to Cd2+ and Zn2+ were slightly affected in several mutants. A quantitative transcriptomics approach was applied to decipher response mechanisms at the transcriptional level further.

WS6 Induces Adult Hippocampal Neurogenesis in Correlation to its Antidepressant Effect on the Alleviation of Depressive-like Behaviors of Rats.

Major depressive disorder (MDD) is one of the most common psychiatric disorders. However, the effective drugs for MDD have not yet been developed. WS6 is originally designed with a similar structure as Resveratrol and Pterostilbene. The present study aims to investigate the neuroprotective and ameliorating effects of WS6 treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results show that CUMS is effective in producing depressive-like behavior in rats as indicated by decreased responses in the locomotor activity, sucrose preference test and increased immobility time. However, WS6 treatment significantly ameliorated these behavioral alterations associated with CUMS-induced depression. Moreover, the reduction in neurogenesis, GABAergic neurons, dendrite complexity, spine density and synaptic plasticity-associate protein 95 (PSD95) by CUMS can be reversed by treatment with WS6. Taken together, this study highlights the neuroprotective and antidepressant-like effects of WS6 against CUMS-induced depression, and suggest a possible mechanism for this protection via changes in neurogenesis within the hippocampus. These finding reveal the therapeutic protection of WS6 for use in clinical trials in the treatment of neuronal deterioration in MDD.

The lateralization of left hippocampal CA3 during the retrieval of spatial working memory.

The hippocampal CA3 contributes to spatial working memory (SWM), but which stage of SWM the CA3 neurons act on and whether the lateralization of CA3 function occurs in SWM is also unknown. Here, we reveal increased neural activity in both sample and choice phases of SWM. Left CA3 (LCA3) neurons show higher sensitivity in the choice phase during the correct versus error trials compared with right CA3 (RCA3) neurons. LCA3 initiates firing prior to RCA3 in the choice phase. Optogenetic suppression of pyramidal neurons in LCA3 disrupts SWM only in the choice phase. Furthermore, we discover that parvalbumin (PV) neurons, rather than cholinergic neurons in the medial septum (DB were cholinergic neurons), can project directly to unilateral CA3. Selective suppression of PV neurons in the MS projecting to LCA3 impairs SWM. The findings suggest that MSPV-LCA3 projection plays a crucial role in manipulating the lateralization of LCA3 in the retrieval of SWM.

Pterostilbene, an active component of the dragon's blood extract, acts as an antidepressant in adult rats.

BACKGROUND: Hippocampal neurogenesis has been widely considered as one of the potential biological mechanisms for the treatment of depression caused by chronic stress. Many natural products have been reported to be beneficial for neurogenesis. OBJECTIVES: The present study is designed to investigate the effect of dragon's blood extract (DBE) and its biologically active compound, pterostilbene (PTE), on hippocampal neurogenesis. METHODS: The male Sprague-Dawley (SD) rats were used in this study, which were maintained on the normal, DBE and PTE diet groups for 4 weeks before dissection in the normal rat model and behavioral testing in the CUS depression rat model. Meanwhile, DMI-treated rats are subcutaneously injected with DMI (10 mg/kg, i.p.). RESULTS: Results revealed that DBE and PTE have the ability to promote hippocampal neurogenesis. DBE and PTE also promoted the proliferation of neural stem cells isolated from the brain of suckling rats. Oral administration of DBE and PTE induced the proliferation, migration, and differentiation of neural progenitor cells (NPCs) in chronic unexpected stressed (CUS) model rats, and improved the behavioral ability and alleviated depress-like symptoms of CUS rats. It was also observed that PTE treatment significantly induced the expression of neurogenesis-related factors, including BDNF, pERK, and pCREB. CONCLUSION: Oral administration of PTE could affect neurogenesis and it is likely to be achieved via BDNF/ERK/CREB-associated signaling pathways.

Discovery of efficient stimulators for adult hippocampal neurogenesis based on scaffolds in dragon's blood.

Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain.