Physiological and pharmacological effects of zinc on rat hippocampal pyramidal neurones in vitro.

The mammalian brain contains an abundance of zinc and stimulation of the mossy fibres in the hippocampus can induce Zn2+ release. However, a physiological role for endogenous zinc in synaptic transmission has not been shown. The present study was undertaken to address this fundamental issue by using electrophysiological techniques, including intracellular and simultaneous extracellular recordings from rat hippocampal brain slices in vitro. Pyramidal neurones were identified by histological methods using intracellular labelling based on the avidin-biotin system. Exogenous zinc (50-300?M) induced the appearance of rhythmically occurring giant depolarizing synaptic potentials (GDPs) in adult hippocampal neurons (n=245). These zinc-induced GDPs were mediated by GABAA receptors and appeared similar to spontaneous large depolarizing potentials which occur naturally in immature CAS neurones (n=160) from young rats (postnatal days 2-12). Selective zinc-chelating agents (CP94 and CP40) based on heterocyclic pyridinones reversibly inhibited these innate GDPs in young neurones in a concentration (1-400μM) dependent manner. The mechanism underlying GDP generation was investigated by examining the effect of zinc on membrane properties and synaptic neurotransmission in adult neurones. Zinc had a wide variety of actions on voltage-operated and/or ligand-gated channels, including i) increasing the membrane input resistance and enhancing cell excitability; ii) augmenting postsynaptic GABAA responses; ill) inhibiting postsynaptic GABAB receptors; iv) increasing the release of GABA; v) inhibiting N-methyl-D-aspartate (NMDA) receptors; vi) potentiating non-NMDA receptor mediated responses; and vii) depressing stimulus-evoked excitatory postsynaptic potentials and population spikes. The long-term potentiation in CA1 and CA3 regions induced by high frequency stimulation was also blocked by zinc. Zinc-induced GDPs occurred in the apparent absence of any functional excitatory synaptic transmission but could be reversibly inhibited by the specific adrenergic β1-receptor antagonist, atenolol. The action of zinc in inducing GDPs was not reproduced by other cations, such as Ba2+, Cd2+, Co2+, Cu2+, Fe2+, Mn2+, Al3+ and a K+ channel blocker 4-aminopyridine. These results provide the first evidence of a physiological role for endogenous zinc in immature hippocampal synaptic neurotransmission and suggest that exogenous zinc can differentially modulate inhibitory and excitatory synaptic transmission in the adult hippocampus

Counting triangles in regular graphs

In this paper, we investigate the minimum number of triangles, denoted by $t(n,k)$, in $n$-vertex $k$-regular graphs, where $n$ is an odd integer and $k$ is an even integer. The well-known Andr\'asfai-Erd\H{o}s-S\'os Theorem has established that $t(n,k)>0$ if $k>\frac{2n}{5}$. In a striking work, Lo has provided the exact value of $t(n,k)$ for sufficiently large $n$, given that $\frac{2n}{5}+\frac{12\sqrt{n}}{5}<k<\frac{n}{2}$. Here, we bridge the gap between the aforementioned results by determining the precise value of $t(n,k)$ in the entire range $\frac{2n}{5}<k<\frac{n}{2}$. This confirms a conjecture of Cambie, de Verclos, and Kang

Spatiotemporal Analysis of Drought Characteristics in Song-Liao River Basin in China

The monthly accumulated precipitation and monthly average temperature of 117 meteorological stations in Song-Liao River Basin (SLRB) were used to calculate the Standardized Precipitation Evapotranspiration Indices (SPEI) to analyze the drought characteristics, including long-term trends, drought affected area, climate abrupt change, intensive drought occurrence regions, and drought durations during 1964–2013 with the support of GIS. The Area Drought Severity (ADS), a comprehensive index, is proposed to assess both the variations of drought degree and the extent of the drought affected area. The results revealed that (1) the drought happening probability and degree are rising and the affected areas of all degrees of drought have an increasing trend during the last 50 years; (2) there is a climate abrupt change which occurred in around 1994, and the area with declining SPEI is larger than that with declining SPI, which could be due to the rising temperature after the climate abrupt change; (3) all degrees of drought occurrence probability increased, and the intensive drought occurrence regions altered from the northern SLRB to the southwestern SLRB after the climate abrupt change; (4) the drought duration increased from 1994, and the increased drought durations occurred in most parts of SLRB

Neuroinflammation and Neurologic Deficits in Diabetes Linked to Brain Accumulation of Amylin

BACKGROUND: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function. METHODS: In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels. RESULTS: Compared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with amylin accumulation in the brain. The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P \u3c 0.05). Large amylin deposits (\u3e50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that amylin deposition in the brain induces a neuroinflammatory response. CONCLUSIONS: Hyperamylinemia promotes accumulation of oligomerized amylin in the brain leading to neurological deficits through an oligomerized amylin-mediated inflammatory response. Additional studies are needed to determine whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline

Macrophages depletion alleviates lung injury by modulating AKT3/GXP4 following ventilator associated pneumonia

BackgroundAKT3 appears to play a role in lung cancer. However, its role in ventilator-associated pneumonia is still unclear. Therefore, this study aimed to investigate the role of AKT3 in macrophages during ventilator-associated pneumonia.MethodsThe mRNA level of AKT3, Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), The data is analyzed using the Xiantao academic analysis tool. Additionally, the roles of AKT3 in ventilator-associated pneumonia (VAP) were investigated through in vivo experiments.ResultsAKT3 was differentially expressed in various normal and tumor tissues. Functional enrichment analysis indicated the immunomodulatory function and inflammatory response of AKT3 in lung cancer. Depletion of macrophages protected against lung epithelial cells and significantly decreased MMP9, MMP19, FTH, and FTL expression levels and increased GPX4 expression levels, while partially reversing the changes in macrophage. Mechanistically, macrophage depletion attenuates ferroptosis of lung epithelial cells by modulating AKT3 following VAP.ConclusionCollectively, this study suggests the need for further validation of the immunoregulatory function of AKT3 in lung cancer. Additionally, macrophage depletion mitigates lung injury by modulating the AKT3/GPX4 pathway in the context of VAP

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

金沢大学医薬保健研究域医学系Stress-induced analgesia (SIA) is a key component of the defensive behavioral "fight-or-flight" response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein-regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA

Density Functional Study of Structures and Electron Affinities of BrO4F/BrO4F−

The structures, electron affinities and bond dissociation energies of BrO4F/BrO4F− species have been investigated with five density functional theory (DFT) methods with DZP++ basis sets. The planar F-Br…O2…O2 complexes possess 3A′ electronic state for neutral molecule and 4A′ state for the corresponding anion. Three types of the neutral-anion energy separations are the adiabatic electron affinity (EAad), the vertical electron affinity (EAvert), and the vertical detachment energy (VDE). The EAad value predicted by B3LYP method is 4.52 eV. The bond dissociation energies De (BrO4F → BrO4-mF + Om) (m = 1–4) and De− (BrO4F− → BrO4-mF− + Om and BrO4F− → BrO4-mF + Om−) are predicted. The adiabatic electron affinities (EAad) were predicted to be 4.52 eV for F-Br…O2…O2 (3A′←4A′) (B3LYP method)

Histone Modifications at Human Enhancers Reflect Global Cell-Type-Specific Gene Expression

The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene1, 2, 3, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome4, 5, 6. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression