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We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus–mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus–mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated–specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.

Introduction Infections could contribute to Alzheimer's disease (AD) neuropathology in human. However, experimental evidence for a causal relationship between infections during the prenatal phase and the onset of AD is lacking. Methods CD‐1 mothers were intraperitoneally received lipopolysaccharide (LPS) with two doses (25 and 50 μg/kg) or normal saline every day during gestational days 15–17. A battery of behavioral tasks was used to assess the species‐typical behavior, sensorimotor capacity, anxiety, locomotor activity, recognition memory, and spatial learning and memory in 1‐, 6‐, 12‐, 18‐, and 22‐month‐old offspring mice. An immunohistochemical technology was performed to detect neuropathological indicators consisting of amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillary acidic protein (GFAP) in the hippocampus. Results Compared to the same‐aged controls, LPS‐treated offspring had similar behavioral abilities and the levels of Aβ42, p‐tau, and GFAP at 1 and 6 months old. From 12 months onward, LPS‐treated offspring gradually showed decreased species‐typical behavior, sensorimotor ability, locomotor activity, recognition memory, and spatial learning and memory, and increased anxieties and the levels of Aβ42, p‐tau, and GFAP relative to the same‐aged controls. Moreover, this damage effect (especially cognitive decline) persistently progressed onwards. The changes in these neuropathological indicators significantly correlated with impaired spatial learning and memory. Conclusions Prenatal exposure to low doses of LPS caused AD‐related features including behavioral and neuropathological changes from midlife to senectitude., Prenatal exposure to low doses of lipopolysaccharide (LPS) caused Alzheimer's disease (AD)‐like features. In later life, LPS‐treated mice showed increased expression of Aβ42, p‐tau, and glial fibrillary acidic protein (GFAP) and these neuropathological indicators correlated with impaired spatial cognition.

In the present study, an effective shot-gun lipidomic methodology was established to determine the glycerophospholipid (GP) molecular species of two species of edible marine whelks (Chlorostoma rusticum and Neverita didyma). Simultaneously, the lipid content, lipid classes, phospholipid (PL) subclasses and fatty acid compositions were also investigated. Over 210 molecular species of GP including glycerophosphocholine, lysoglycerophosphocholine, glycerophosphoethanolamine, lysoglycerophosphoethanolamine, glycerophosphoserine, lysoglycerophosphoserine, glycerophosphoinositol and lysoglycerophosphoinositol were characterized in the two abovementioned whelk species. The predominant GP molecular species contained n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), especially docosahexaenoic acid and eicosapentaenoic acid. Meanwhile, PL (57.70-58.86% of total lipids) and PUFA (21.69-37.68% of total FA) take large proportions in whelk lipids. Among PL, phosphatidylcholine (50.58-52.41 mol%) and phosphatidylethanolamine (27.67-32.73 mol%) were dominant. Therefore, marine whelks turn out to be promising source of n-3 LC-PUFA existed in PL form and thus directly contribute to the health benefits of consumer.

The objective of this study was to evaluate the change of lipids in two whelk samples during cold storage. Results showed that the peroxide value (PV) and thiobarbituric acid reactive substance (TBARS) increased while the percentage of polyunsaturated fatty acid decreased, indicating that lipid oxidation occurred. The cold storage significantly reduced the levels of triacylglycerol (TAG), polar lipid (PoL), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) but increased the levels of acid value (AV), free fatty acid (FFA) and monoacylglycerol, suggesting the hydrolysis of lipids. Moreover, the results showed that the lipoxygenase, acid lipase and phospholipase contributed to the hydrolysis and oxidation of lipids in the two whelks. Additionally, partial least squares discriminant analysis showed PC was positively correlated with PE, PoL and TAG, but negatively correlated with AV, FFA, PV and TBARS, indicating there is a close relationship between hydrolysis and oxidation of lipids.

Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile and hypoxic regions a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress, due to downregulation of the E3 ligase, RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are preferentially sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be necessary to overcome resistance to therapies caused by intratumoral heterogeneity.

Summary The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert−/−) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment., Highlights • Tert gene knockout causes extremely poor ability in spatial memory formation • Dendritic development and neuritogenesis are impaired in Tert−/− mice • TERT is required for neural circuit integration of hippocampal newborn neurons • TERT regulates spatial memory formation in an activity-independent manner, In this article, Qi-Gang Zhou and colleagues show that spatial memory formation, neural development including dendritic development and neuritogenesis, and neural circuit integration are impaired in Tert gene knockout mice. Hippocampal TERT accounts for these phenotypes in a reverse transcription activity-independent manner.

Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption—both sensitive to heterogeneous values. Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods. Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both in vitro and in vivo, to be crucial in tumorigenesis, e.g., alcohol metabolism (ADH1B), chromosome remodeling (NCAPH) and complement system (Adipsin). Together, we present a sharper tool to navigate large-scale expression data and gain new mechanistic insights into tumorigenesis.

Whelks Neptunea arthritica cumingi Crosse and Neverita didyma were processed by hot air drying and changes of thei lipids and the mechanism involved were evaluated by analyzing peroxide value, thiobarbituric acid-reactive substances, total oxidation value, fatty acid composition, activities of lipases and lipoxygenase (LOX), as well as contents of triacylglycerol (TAG), free fatty acid (FFA), phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The processing significantly decreased the contents of PC, PE and TAG but increased the content of FFA. The presence of acid lipase and phospholipase in whelk tissues and their activity preservation during processing suggest that the enzymes may help hydrolyze lipids. By contrast, the reduction of PC, PE and TAG was more pronounced than the increase in FFA in whelk tissues upon processing, indicating the oxidative degradation of FFA. LOX may play a role in lipid oxidation due to the stability of the starting components during processing.

The gut microbiota is composed of a large number of microbes, usually regarded as commensal bacteria. It has become gradually clear that gastrointestinal microbiota affects gut pathophysiology and the central nervous system (CNS) function by modulating the signaling pathways of the microbiota-gut-brain (MGB) axis. This bidirectional MGB axis communication primarily acts through neuroendocrine, neuroimmune, and autonomic nervous systems (ANS) mechanisms. Accumulating evidence reveals that gut microbiota interacts with the host brain, and its modulation may play a critical role in the pathology of neuropsychiatric disorders. Recently, neuroscience research has established the significance of gut microbiota in the development of brain systems that are essential to stress-related behaviors, including depression and anxiety. Application of modulators of the MGB, such as psychobiotics (e.g., probiotics), prebiotics, and specific diets, may be a promising therapeutic approach for neuropsychiatric disorders. The present review article primarily focuses on the relevant features of the disturbances of the MGB axis in the pathophysiology of neuropsychiatric disorders and its potential mechanisms.

Using a lentivirus-mediated labeling method, we investigated whether the adult hippocampus retains long-lasting, self-renewing neural stem cells (NSCs). We first showed that a single injection of a lentiviral vector expressing a green fluorescent protein (LV PGK-GFP) into the subgranular zone (SGZ) of the adult hippocampus enabled an efficient, robust, and long-term marking of self-renewing NSCs and their progeny. Interestingly, a subset of labeled cells showed the ability to proliferate multiple times and give rise to Sox2+ cells, clearly suggesting the ability of NSCs to self-renew for an extensive period of time (up to 6 months). In addition, using GFP+ cells isolated from the SGZ of mice that received a LV PGK-GFP injection 3 months earlier, we demonstrated that some GFP+ cells displayed the essential properties of NSCs, such as self-renewal and multipotency. Furthermore, we investigated the plasticity of NSCs in a perforant path transection, which has been shown to induce astrocyte formation in the molecular layer of the hippocampus. Our lentivirus (LV)-mediated labeling study revealed that hippocampal NSCs are not responsible for the burst of astrocyte formation, suggesting that signals released from the injured perforant path did not influence NSC fate determination. Therefore, our studies showed that a gene delivery system using LVs is a unique method to be used for understanding the complex nature of NSCs and may have translational impact in gene therapy by efficiently targeting NSCs.

Telomerase, a specialized ribonucleoprotein enzyme complex, maintains telomere length at the 3' end of chromosomes, and functions importantly in stem cells, cancer and aging. Telomerase exists in neural stem cells (NSCs) and neural progenitor cells (NPCs), at a high level in the developing and adult brains of humans and rodents. Increasing studies have demonstrated that telomerase in NSCs/NPCs plays important roles in cell proliferation, neuronal differentiation, neuronal survival, and neuritogenesis. In addition, recent works have shown that telomerase reverse transcriptase (TERT) can protect newborn neurons from apoptosis and excitotoxicity. However, to date, the link between telomerase and diseases in the central nervous system (CNS) is not well reviewed. Here we analyze the evidence and summarize the important roles of telomerase in the CNS. Understanding the roles of telomerase in the nervous system is not only important to gain further insight into the process of the neural cell life cycle, but would also provide novel therapeutic applications in CNS diseases such as neurodegenerative condiction, mood disorders, aging, and other ailments.

Sea cucumber is a “healthy” food. Although previous studies have suggested that sea cucumber might serve as a potential rich source of polyunsaturated fatty acids (PUFAs) enriched phospholipid (PL), the molecular species of its PL has rarely been reported. In this study, some 200 glycerophospholipid (GP) species belonging to seven classes in processing by-products (spawns and intestines) of sea cucumber (Stichopus japonicus) were characterized for the first time. Most of the dominant GP species contained PUFAs, especially eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (AA, C20:4n-6). Meanwhile, the lipids contained high levels of PUFA (25.35–45.12% of total FAs) and polar lipid (65.55–85.95% of total lipids) but low levels of cholesterol (0.63–2.26% of total lipids). Among PL, phosphatidylcholine (38.34–65.56 mol%) was dominant. Therefore, PUFA enriched PL in sea cucumber may account for their nutritional and health beneficial effects. Meanwhile, by-products of Stichopus japonicus byproducts provide great potential as health-promoting food ingredients.

Summary In neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

We previously showed increased growth associated protein 43 (GAP-43) expression in brain samples resected from patients with cortical dysplasia (CD), which was correlated with duration of epilepsy. Here, we used a rat model of CD to examine the regulation of GAP-43 in the brain and serum over the course of epileptogenesis. Baseline GAP-43 expression was higher in CD animals compared to control non-CD rats. An acute seizure increased GAP-43 expression in both CD and control rats. However, GAP-43 expression decreased by day 15 post-seizure in control rats, which did not develop spontaneous seizures. In contrast, GAP-43 remained up-regulated in CD rats, and over 50% developed chronic epilepsy with increased GAP-43 levels in their serum. GAP-43 protein was primarily located in excitatory neurons, suggesting its functional significance in epileptogenesis. Inhibition of GAP-43 expression by shRNA significantly reduced seizure duration and severity in CD rats after acute seizures with subsequent reduction in interictal spiking. Serum GAP-43 levels were significantly higher in CD rats that developed spontaneous seizures. Together, these results suggest GAP-43 as a key factor promoting epileptogenesis, a possible therapeutic target for treatment of progressive epilepsy and a potential biomarker for epilepsy progression in CD.

Introduction: With the widespread use of cephalosporins, Enterobacter cloacae has become an increasingly important pathogen of nosocomial infections, which causes bacterial infectious diseases involving multiple organ systems. The presence of carbapenem-resistant strains has resulted in problems in the current clinical anti-infective treatment. The current study reports on four cases of carbapenem-resistant E. cloacae secretion infection in order to provide suggestions for the detection and treatment of these pathogen infections. Case Presentation: Investigation of 4 cases was conducted at tertiary care hospitals, and baseline data, treatment and outcomes were collected for patients with carbapenem-resistant E. cloacae infection. The strains of burn injury and diabetic foot infection were retrieved from specimens by culture-based methods, and antibiotic sensitivity test was conducted on Vitek 2. All strains showed minimum inhibitory concentration (MIC) values for ertapenem, imipenem, and meropenem of less than 4 μg/mL. The four strains of E. cloacae produced IMP-8 type carbapenemase confirmed by PCR and sequence analysis. After the selection of reasonable antibiotic treatment, the patient`s condition had improved and they were discharged from the hospital. Conclusions: Low MIC value makes it difficult to detect IMP-8-harboring strains by traditional susceptibility test; molecular biology techniques may be mandatory for detection of carbapenem resistant isolates. It is very important to treat patients with reasonable antimicrobial based on susceptibility results.

Changes in pig fertility have occurred as a result of domestication, but are not understood at the level of genetic variation. To identify variations potentially responsible for prolificacy, we sequenced the genomes of the highly prolific Taihu pig breed and four control breeds. Genes involved in embryogenesis and morphogenesis were targeted in the Taihu pig, consistent with the morphological differences observed between the Taihu pig and others during pregnancy. Additionally, excessive functional non-coding mutations have been specifically fixed or nearly fixed in the Taihu pig. We focused attention on an oestrogen response element (ERE) within the first intron of the bone morphogenetic protein receptor type-1B gene ( BMPR1B ) that overlaps with a known quantitative trait locus (QTL) for pig fecundity. Using 242 pigs from 30 different breeds, we confirmed that the genotype of the ERE was nearly fixed in the Taihu pig. ERE function was assessed by luciferase assays, examination of histological sections, chromatin immunoprecipitation, quantitative polymerase chain reactions, and western blots. The results suggest that the ERE may control pig prolificacy via the cis-regulation of BMPR1B expression. This study provides new insight into changes in reproductive performance and highlights the role of non-coding mutations in generating phenotypic diversity between breeds.

Whelk has been exploited commercially as a delicacy for a long time. Although previous studies have suggested that whelk might serve as a potential rich source of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA) enriched phospholipid (PL), the molecular species profile of the PL have not been reported yet. In this study, more than 220 molecular species of glycerophospholipid (GP) belonging to eight classes including glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoinositol, lysoglycerophosphocholine, lysoglycerophosphoethanolamine, lysoglycerophosphoserine and lysoglycerophosphoinositol in three species of edible whelks (Buccinium yokomaruae, Neptunea arthritica cumingi Cosse and Volutharpa ampullaceal) were identified for the first time by using direct infusion tandem mass spectrometric method. Most of the predominant GP molecular species contained n-3 LC-PUFA, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Meanwhile, the whelk lipids contained a high proportion of PL (32.92–55.55% of total lipids) and PUFA (30.45–41.42% of total FA). Among PL, phosphatidylcholine (44.18–65.49 mol%) was dominant.

Our previous study found that serotonin 1A receptor (5-HT1aR) is an endogenous suppressor of nNOS expression in the hippocampus, which accounts for anxiolytic effect of fluoxetine. However, the precise molecular mechanism remains unknown. By using 8-OH-DPAT, a selective 5-HT1aR agonist, NAN-190, a selective 5-HT1aR antagonist, and U0126, an Extracellular Regulated Protein Kinases (ERK) phosphorylation inhibitor, we investigated the role of ERK in 5-HT1aR-nNOS pathway. Western blots analysis demonstrated that 5-HT1aR activation up-regulated the level of phosphorylated ERK (P-ERK) beginning at 5 min and down-regulated the expression of nNOS beginning at 20 min. Meanwhile, blockage of 5-HT1aR resulted in a decrease in P-ERK beginning at 20 min and caused an increase in nNOS expression beginning at 6 h. Although U0126 itself did not alter nNOS expression and activity, NO level, and anxiety-related behaviors, the treatment totally reversed 8-OH-DPAT-induced reduction in nNOS expression and function, and anxiolytic effect. Besides, our data showed that ERK phosphorylation was essential for 5-HT1aR activation-induced cAMP responsive element binding protein (CREB) phosphorylation, hippocampal neurogenesis and synaptogenesis of newborn neuron. Our study suggests a crucial role of ERK phosphorylation in the regulation of nNOS expression by 5-HT1aR, which is helpful for understanding the mechanism of 5-HT1aR-based anxiolytic treatment.

Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus.

Root nodule symbiosis (RNS) is one of the most efficient biological systems for nitrogen fixation\ud and it occurs in 90% of genera in the Papilionoideae, the largest subfamily of legumes. Most\ud papilionoid species show evidence of a polyploidy event occurred approximately 58 million years\ud ago. Although polyploidy is considered to be an important evolutionary force in plants, the role of\ud this papilionoid polyploidy event, especially its association with RNS, is not understood. In this\ud study, we explored this role using an integrated comparative genomic approach and conducted\ud gene expression comparisons and gene ontology enrichment analyses. The results show the\ud following: (1) approximately a quarter of the papilionoid-polyploidy-derived duplicate genes are\ud retained; (2) there is a striking divergence in the level of expression of gene duplicate pairs derived\ud from the polyploidy event; and (3) the retained duplicates are frequently involved in the processes\ud crucial for RNS establishment, such as symbiotic signalling, nodule organogenesis, rhizobial\ud infection and nutrient exchange and transport. Thus, we conclude that the papilionoid polyploidy\ud event might have further refined RNS and induced a more robust and enhanced symbiotic system.\ud This conclusion partly explains the widespread occurrence of the Papilionoideae.

Knowledge of genetic diversity and fine-scale spatial genetic structure (SGS) at different age stages of small isolated populations is important for understanding population dynamics and developing effective conservation measures for fragmented populations. In this study, we used a small, isolated population of Sinojackia huangmeiensi as a case study to investigate the change in the levels of genetic diversity and SGS at different age stages. We mapped and genotyped 60 adults,175 saplings, 198 seedlings using eight microsatellite markers to detect the genetic diversity, SGS and pollen and seed dispersal patterns in a 80 m × 160 m transect located in an original secondary forest surrounded by farmlands. No significant differences in genetic diversity were found among the three life stages, and a significant heterozygote deficiency in the population may result from substantial biparental inbreeding. We found significant fine-scale spatial structure at different age stages within 10 m, suggesting that seed dispersal mainly occurred near a mother tree. Seed dispersal distance and pollen dispersal distance were 9.07±13.38 and 23.81±23.60 m, respectively, and ‘L’ 第 4期 阮咏梅等: 黄梅秤锤树孤立居群的遗传多样性及其小尺度空间遗传结构 461 shaped curves were observed in both pollen dispersal and seed dispersal patterns. The spatial distribution of the different age stages is most likely the result of little overlap in seed rain, self-thinning, biparental inbreeding and limited gene flow. Our results have important implications for conservation of extant population of S. huangmeiensis. Measures for promoting pollen flow and increasing survival rate of seedlings should be considered for in situ conservation. The presence of SGS in this fragmented population implies that seeds for ex situ conservation should be collected from trees at least 10 m apart to reduce genetic similarity between neighboring individuals.

Seed oils provide a renewable source of food, biofuel and industrial raw materials that is important for humans. Although many genes and pathways for acyl-lipid metabolism have been identified, little is known about whether there is a specific mechanism for high-oil content in high-oil plants. Based on the distinct differences in seed oil content between four high-oil dicots (20~50%) and three low-oil grasses (

Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the mother-self during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15–17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, phosphorylated tau, presynaptic proteins synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice’s abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β42, phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer’s disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging.

The floral development of Phyllanthus chekiangensis has been studied by scanning electron microscopy. The perianth organs are initiated in two whorls, dimerous in male flowers and trimerous in female flowers, with a longer plastochron between whorls than between the organs within a whorl. Male flowers have two stamens. The prominent connective protrusions begin development simultaneously with the floral disk. The disk is two-lobed in male flowers but continuous in female flowers. In female flowers, the developing gynoecium remains open relatively long, so the developing ovules are visible from the outside for some time. The direction of the hemitropous ovules in the carpels is antitropous (epitropous). Two small obturators are formed per carpel, one above each ovule. The prominent nucellar beak extends far beyond the “micropyle”. A micropyle in the classical sense formed by integuments closing over the nucellus apex is not present at any stage of development. Thus, it is not correct to say that the nucellar beak “grows through the micropyle”. The exposed nucellar beak continues the curvature of the antitropous (epitropous) ovule and becomes contiguous with the obturator. The unusual length of the nucellar beak may be a potential synapomorphy of the enlarged Phyllanthus clade as inferred from molecular phylogenetics.

Starch is the most widespread and abundant storage carbohydrate in crops and its production is critical to both crop yield and quality. In regard to the starch content in the seeds of crop plants, there is a distinct difference between grasses (Poaceae) and dicots. However, few studies have described the evolutionary pattern of genes in the starch biosynthetic pathway in these two groups of plants. In this study, therefore, an attempt was made to compare evolutionary rate, gene duplication, and selective pattern of the key genes involved in this pathway between the two groups, using five grasses and five dicots as materials. The results showed 1) distinct differences in patterns of gene duplication and loss between grasses and dicots; duplication in grasses mainly occurred before the divergence of grasses, whereas duplication mostly occurred in individual species within the dicots; there is less gene loss in grasses than in dicots, 2) a considerably higher evolutionary rate in grasses than in dicots in most gene families analyzed, and 3) evidence of a different selective pattern between grasses and dicots; positive selection may have occurred asymmetrically in grasses in some gene families, for example, ADP-glucose pyrophosphorylase small subunit. Therefore, we deduced that gene duplication contributes to, and a higher evolutionary rate is associated with, the higher starch content in grasses. In addition, two novel aspects of the evolution of the starch biosynthetic pathway were observed.

Age-related impairment of learning and memory is a common phenomenon in humans and animals, yet the underlying mechanism remains unclear. We hypothesize that a small ubiquitin-related modifier (Sumo) might correlate with age-related loss of learning and memory. To test this hypothesis, the present study evaluated age-related spatial learning and memory in C57BL/6 mice (25 aged 7 months and 21 aged 25 months) using a radial six-arm water maze (RAWM). After the behavioral test, the protein expression of Sumo3 was determined in different brain regions using Western blotting. The results showed that the 25-month-old mice had longer latency and a higher number of errors in both learning and memory phases in the RAWM task than the 7-month-old mice. Compared to the latter, the former's level of Sumo3 protein was significantly increased in the dorsal and ventral hippocampus. For the 25-month-old mice, the number of errors and the latency in the learning phase negatively correlated with the Sumo3 level in the dorsal hippocampus. These results suggest that increased Sumo3 in the hippocampus may be correlated with spatial learning ability in old C57BL/6 mice.

Wild Rosa resources in Yunnan are very abundant and hold many important and useful traits for improving modern rose. However, many of them have no cytological data and few were karyologically analysed. In this article, karyological study of 24 wild Rosa taxa belonging to different sections was carried out by means of traditional squashing and pressing. The chromosome number of 8 taxa and karyotypes of most studied ones were reported for the first time. 22 resources were diploids with 14 chromosomes (2n = 2x = 14), while Rosa moyesii Hemsl. et Wils. and Rosa macrophylla Lindl. from Sect. Cinnamomeae DC. were hexaploids with 42 chromosomes (2n = 6x = 42). Only type 1A and type 2A been found, karyotypes of genus Rosa in Yunnan were symmetric. Also, the studied taxa differed much from each other in chromosome length, position of centromere, satellite position and satellite number, etc. The results implied that wild Rosa germplasm in Yunnan were rich in karyologcal diversity, and polyploidization might have played and were still playing very important roles in the evolution and speciation in genus Rosa, mainly in Sect. Cinnamomeae in alpine areas of northwestern Yunnan. The cytological data would supply chromosomal proofs not only for the taxonomy, phylogeny and evolution of genus Rosa in this special geological area, but also for the exploitation of useful traits of wild Rosa into the breeding of new cultivars.

Telomere and telomerase alterations have been reported in mood disorders. However, the role of telomerase in depression remains unclear. Here we show that chronic mild stress (CMS) led to a significant decrease in telomerase reverse transcriptase (TERT) level and telomerase activity in the hippocampus. Treatment with antidepressant fluoxetine reversed the CMS-induced TERT and telomerase activity changes. Inhibiting telomerase by systemic administration (100 mg · kg−1· d−1, i.p., for 14 d), intrahippocampal microinjection (0.7 μmol, 2 μl), or infusion (using an osmotic minipump, 0.134 μg/μl, 0.25 μl/h) of 3′-azido-deoxythymidine (AZT) resulted in depression-like behaviors and impaired hippocampal neurogenesis in mice. In contrast, overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse TERT (Ad-mTERT-GFP) led to neurogenesis upregulation, produced antidepressant-like behaviors, and prevented the CMS-induced behavioral modifications. Disrupting neurogenesis in the dentate gyrus by X-irradiation (15 Gy) of a restricted region of mouse brain containing the hippocampus abolished the antidepressant-like effect of Ad-mTERT-GFP. Additionally, AZT had no effect on DNA polymerase activity and did not cause cell damagein vitroandin vivo. Microinjection of AZT into the subventricular zone of lateral ventricle (0.7 μmol, 2 μl) inhibited local neurogenesis but had no behavioral effect. These results suggest that hippocampal telomerase is involved in the modulation of depression-related behaviors, possibly by regulating adult neurogenesis.

It has been demonstrated that neuronal nitric oxide synthase (nNOS) negatively regulates adult neurogenesis. However, the cellular and molecular mechanisms underlying are poorly understood. Here, we show that nNOS from neural stem cells (NSCs) and from neurons play opposite role in regulating neurogenesis. The NSCs treated with nNOS inhibitor N5-(1-imino-3-butenyl)-L- ornithine (L-VNIO) or nNOS gene deletion exhibited significantly decreased proliferation and neuronal differentiation, indicating that NSCs-derived nNOS is essential for neurogenesis. The NSCs cocultured with neurons displayed a significantly decreased proliferation, and deleting nNOS gene in neurons or scavenging extracellular nitric oxide (NO) abolished the effects of coculture, suggesting that neurons-derived nNOS, a source of exogenous NO for NSCs, exerts a negative control on neurogenesis. Indeed, the NSCs exposed to NO donor DETA/NONOate displayed decreased proliferation and neuronal differentiation. The bidirectional regulation of neurogenesis by NSCs- and neurons-derived nNOS is probably related to their distinct subcellular localizations, mainly in nuclei for NSCs and in cytoplasm for neurons. Both L-VNIO and DETA/NONOate inhibited telomerase activity and proliferation in wild-type (WT) but not in nNOS−/− NSCs, suggesting a nNOS-telomerase signaling in neurogenesis. The NSCs exposed to DETA/NONOate exhibited reduced cAMP response element binding protein (CREB) phosphorylation, nNOS expression, and proliferation. The effects of DETA/NONOate were reversed by forskolin, an activator of CREB signaling. Moreover, disrupting CREB phosphorylation by H-89 or LV-CREB133-GFP simulated the effects of DETA/NONOate, and inhibited telomerase activity. Thus, we conclude that NSCs-derived nNOS stimulates neurogenesis via activating telomerase, whereas neurons-derived nNOS represses neurogenesis by supplying exogenous NO that hinders CREB activation, in turn, reduces nNOS expression in NSCs.

Increasing evidence suggests that 5-HT1Areceptor (5-HT1AR) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT1AR in these diseases remains unknown. Here, we show that 5-HT1AR-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT1AR-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7-NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 μg/1.0 μl) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 μg/100 μl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 μg/1.0 μl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 μg/1.0 μl). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 μg/1.0 μl), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT1AR agonists and SSRIs.

Six new terpenoids, including three diterpenoids ( 1- 3), one norditerpenoid ( 4) and two sesquiterpenoids ( 11 and 12), were isolated from the roots of CHLORANTHUS HENRYI. The structures were elucidated mainly by 1D, and 2D NMR and MS experiments, and their relative configurations were determined by NOE techniques.

Several lines of evidence suggest involvement of NMDA receptors (NMDARs) in the regulation of neurogenesis in adults and the formation of spatial memory. Functional properties of NMDARs are strongly influenced by the type of NR2 subunits incorporated. In adult forebrain regions such as the hippocampus and cortex, only NR2A and NR2B subunits are available to form the receptor complex with NR1 subunit. NR2B is predominant NR2 subunit in any of rat or human neural stem cells (NSCs). Thus, we suppose that NR2B-containing NMDAR should be critical in regulating adult neurogenesis, and thereby playing a role in the formation of spatial memory. In the cultured NSCs derived from the embryonic brain of rats, NR2B subunit-specific NMDAR antagonist Ro25-6981 increased cell proliferation, whereas MK-801, non-selective open-channel blocker of NMDARs, inhibited cell proliferation. Blockade of NR2B-containing NMDAR stimulated neurogenesis in the adult hippocampus and facilitated the formation of spatial memory. The enhanced spatial memory dropped back to base level when the NR2B antagonist-induced neurogenesis was neutralized by 3'-azido-deoxythymidine, a telomerase inhibitor. In addition, blockade of NR2B inhibited neuronal nitric oxide synthase (nNOS) enzymatic activity. In null mutant mice lacking nNOS gene (nNOS-/-), the effects of NR2B antagonist on neurogenesis disappeared. Moreover, nitric oxide donor DETA/NONOate attenuated and nNOS inhibitor 7-nitroindazole enhanced the effect of Ro 25-6981 on NSCs proliferation. Our findings suggest that NR2B-containing NMDAR subtypes negatively regulate neurogenesis in the adult hippocampus by activating nNOS activity and thereby hinder the formation of spatial memory.

It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.

β-catenin is closely associated with proliferation, differentiation, invasion and metastasis of tumor cells. C-myc is proved to be abnormally expressed in various kinds of malignant neoplasmas. This study is aimed to investigate the features of β-catenin and C-myc expressions in thymoma and the corresponding clinical significance. Immunochemistry was used to detect the features of expressions of β-catenin and C-myc in thymoma and normal thymus. Of the 105 samples, according to Beratz classification, there were: epithelial type 34; lymphocyte type 35; mixed type 31 and shuttle cell type 5. According to Masaoka classification, there were: stage 1: 38; stage 2: 32; stage 3: 20 and stage 4: 15. According to WHO classification, there were: type A 20; type AB 19; type B1 21; type B2 17; type B3 13 and type C 15. Different ways of expression was revealed in different stages of thymomas. With the progress of thymoma, the expression of β-catenin on cell membrane decreased, while increased in cytoplasma and nucleus, even with nucleus shift. The expression of C-myc increased in invasive thymoma. Abnormal expression of β-catenin and C-myc increased, with significant difference(P

Objective: To investigate the mechanism of carcinogenesis, invasion and metastasis. Methods: The expressions of adhesive molecule and adhesive structure in v-k-ras transformed normal rat kidney cells (KNRK) were detected with a variety of molecular biological techniques, including cell culture, immunofluorescence labeling, electron microscopy, polyacrylamide gel electrophoresis, and protein blotting, and compared with normal rat kidney (NRK) cells. Results: The significantly shortened doubling time, remarkably active proliferation ability in soft agar, and invasive growth in the abdomen of nude rat, demonstrated the malignant biological behaviors of KNRK cells. In KNRK cells, the adhesive molecules, P-cadherin, α and β catenin, actin, and adhesive structures, the adhesive junction and gap junction, were all abnormally expressed. And cell aggregation was significantly decreased. The aggregation ability disappeared at 20°C, and became active with a suitable amount of calcium solution. Conclusion: Following the transfection of virus K-ras gene, normal cells were transformed into malignant cells. In early stage of cancer, the variation of adhesive ability may be one of the vital factors underlying tumorigenesis, invasion and metastasis.

Chromosome behavior during meiosis of the tetraploid Isoetes sinensis was observed to be similar to that of basic diploid Isoetes species. This observation was consistent with the previous report that polyploid species of Isoetes are allopolyploids. Meiosis was generally similar in both megaspore and microspore mother cells, but differences were observed. Due to the smaller size of the microspore mother cells, during prophase I, chromosomes are not as dispersed as those in megaspore mother cells. Cytomixis was observed in all stages of meiosis in microspore mother cells, but it was not seen at any stage of meiosis in megaspore mother cells. Cytomixis, lagging chromosomes, chromosome bridges, chromosome fragments, and micronuclei, observed during meiosis in I. sinensis, can affect sexual reproduction, but it does not appear to be a major cause of population decline in this species. The major cause of decline is habitat degradation from human disturbance. The few remaining populations of the Chines...

Lung cancer has long been one of the most serious types of malignant tumor, and is associated with high incidence and mortality rates. Despite advancements in the comprehensive treatment of the disease, particularly with targeted therapeutic agents, there has been little improvement in the 5-year survival rates of patients. One of the leading causes of mortality in lung cancer is the lack of effective early diagnostic criteria. On this basis, the present study aimed to identify an index with potential in the early diagnosis and prognosis of lung cancer. The current study determined the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and AXL proteins in non-small cell lung cancer (NSCLC) tumor samples, and performed prognostic analysis of the collected clinical data to identify any association. In addition, RNA interference was performed to silence the expression of hnRNP A2/B1, allowing evaluation of its molecular and cellular functions, and determination of the mechanism of hnRNP A2/B1 in NSCLC by means of AXL mediation. It was identified that the positive expression rate of hnRNP A2/B1 and AXL proteins were significantly higher in NSCLC compared with paracancerous lung tissues (P

Free radical production contributes to the early ischemic response and the neuroinflammatory response to injury initiates the second wave of cell death following ischemic stroke. Edaravone is a free radical scavenger, and borneol has shown anti-inflammatory effect. We investigated the synergistic effect of these two drugs in the rat model of transient cerebral ischemia. Edaravone scavenged OH, NO and ONOO─ concentration-dependently, and borneol inhibited ischemia/reperfusion-induced tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expressions. In the rat model of transient cerebral ischemia and reperfusion, the combination of edaravone and borneol significantly ameliorated ischemic damage with an optimal proportion of 4:1. Emax (% inhibition) of edaravone, borneol and two drugs in combination was 55.7%, 65.8% and 74.3% respectively. ED50 of edaravone and borneol was 7.17 and 0.36 mg/kg respectively. When two drugs in combination, ED50 was 0.484 mg/kg, in which edaravone was 0.387 mg/kg (ineffective dose) and borneol was 0.097 mg/kg (ineffective dose). Combination index (CI)

Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children ( n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between −0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.)

Sinojackia huangmeiensis J. W. Ge & X. H. Yao, a new species of Sinojackia Hu from Hubei Province, central China, is described and illustrated. It is similar to S. xylocarpa Hu. The new species differs from S. xylocarpa, however, in its smaller flowers with broadly ovate petals and smaller fruit bearing a papillate short beak.

The accumulation of the amyloid-β peptide (Aβ) into amyloid plaques, an essential event in Alzheimer's disease (AD) pathogenesis, has caused researchers to seek compounds that physiologically bind Aβ and modulate its aggregation and neurotoxicity. In order to develop new Aβ-specific peptides for AD, a randomized 12-mer peptide library with Aβ₁₋₁₀ as the target was used to identify peptides in the present study. After three rounds of selection, specific phages were screened, and their binding affinities to Aβ₁₋₁₀ were found to be highly specific. Finally, a special peptide was synthesized according to the sequences of the selected phages. In addition, the effects of the special peptide on Aβ aggregation and Aβ-mediated neurotoxicity in vitro and in vivo were assessed. The results show that the special peptide not only inhibited the aggregation of Aβ into plaques, but it also alleviated Aβ-induced PC12 cell viability and apoptosis at appropriate concentrations as assessed by the cell counting kit-8 assay and propidium iodide staining. Moreover, the special peptide exhibited a protective effect against Aβ-induced learning and memory deficits in rats, as determined by the Morris water maze task. In conclusion, we selected a peptide that specifically binds Aβ₁₋₁₀ and can modulate Aβ aggregation and Aβ-induced neuronal damage. This opens up possibilities for the development of a novel therapeutic approach for the treatment of AD.

We sought to construct the adenoviral vector carrying the gene encoding mouse telomerase reverse transcriptase (mTERT), as well as detect its expression and effect on the proliferation of neuronal stem cells. mTERT was amplified by RT-PCR and then the eukaryotic expression vector of pDC-EGFP-TERT was constructed. After DNA sequence analysis, we detected that there were 293 cells transfected with pDC-EGFP-TERT and helper adenovirus plasmid pBHG lox ΔE1, and three Cre using Lipofectamine 2000 mediation, named Ad-mTERT-GFP, to package adenoviral particles. The Ad-mTERT-GFP was used to infect neuronal stem cells and then the expression and activity of mTERT were detected. In addition, Bromodeoxyuridine labeling test identified the impact of mTERT overexpression on proliferation of neuronal stem cells. The recombinant adenoviral vector confirmed that mTERT was successfully constructed. Overexpression of mTERT stimulated the proliferation of neuronal stem cells both in vitro and in vivo. mTERT overexpression via adenoviral vector carrying mTERT cDNA upregulated the ability of proliferation in neuronal stem cells.

Objectives: The primary purpose of this study was to investigate the in vitro and in vivo effect of survivin interference RNA (siRNA) on non-small cell lung cancer. Methods: Lentivirus was used as a vector to transfer siRNA into human lung cancer A549 cells. The proliferation of the cancer cells was assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The lentivirus-mediated siRNA was also injected into the transplanted A549 tumor tissues in mice. Tumour growth was assessed after 11 injections over a period of 21 days. Results: Compared with the placebo and the blank lentiviral vector groups, the siRNA treatment group had reduced cell growth rate following 4 days of the treatment (P < 0.01). The average size of the transplanted A549 tumours in the siRNA treatment group (0.75±0.16 cm3, n=8) was smaller than in the placebo (2.09±0.22 cm3, n=6) or the blank lentivrial vector groups (1.89±0.18 cm3, n=6) (P < 0.01). The tumour growth inhibition rate in the siRNA groups was 46.1%. Conclusion: Lentivirus-mediated siRNA therapy inhibits the growth of human lung cancer cells in vitro. The siRNA therapy also suppresses the growth of the transplanted lung cancer in mice.

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)-derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over-expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS-induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS-/-) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS-/- mice exhibited antidepressant-like properties. Our findings suggest that nNOS over-expression in the hippocampus is essential for chronic stress-induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.

Spatial cognitive impairment is common after stroke insults. Voluntary exercise could improve the impaired spatial memory. Newly generated neurons in the dentate gyrus are necessary for the acquisition of new hippocampus-dependent memories. However, it is not well known whether voluntary exercise after stroke promotes neurogenesis in the adult dentate gyrus, thereby promoting spatial memory recovery. Here, we examined in mice subjected to focal cerebral ischemia the effect of voluntary or forced exercise on neurogenesis in the ischemic dentate gyrus and spatial memory. Exposure to voluntary wheel running after stroke enhanced newborn cell survival and up-regulated the phosphorylation of cAMP response element binding protein (CREB) in the dentate gyrus and reversed ischemia-induced spatial memory impairment. However, the enhanced newborn cell survival and CREB phosphorylation in the dentate gyrus and improved spatial memory were not observed in the mice exposed to forced swimming. Moreover, there was a significant correlation between the total number of surviving newborn cells in the dentate gyrus and the ability of mice to locate the platform in the Morris water maze. These results suggest that, in the adult mice, exposure to voluntary exercise after ischemic stroke may promote newborn cells survival in the dentate gyrus by up-regulating CREB phosphorylation and consequently restore impaired hippocampus-dependent memory.

A new Daphniphyllum alkaloid daphnicyclidin L (1), containing a rare cyclopentadienyl anion, which is stabilized as a zwitterion by an internal iminium counterion, was isolated from the stem barks of Daphniphyllum macropodum Miq., together with four known alkaloids: daphnicyclidin D (2), daphnicyclidin H (3), deoxyyuzurimine (4), and yuzurimine (5). The structures were elucidated on the basis of spectroscopic data. The configuration of 1 was elucidated by single-crystal X-ray diffraction crystallography.