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The white matter (WM) functional network changes offers insights into the potential pathological mechanisms of certain diseases, the alterations of WM functional network in idiopathic generalized epilepsy (IGE) remain unclear. We aimed to explore the topological characteristics changes of WM functional network in childhood IGE using resting-state functional Magnetic resonance imaging (MRI) and T 1 -weighted images. A total of 84 children (42 IGE and 42 matched healthy controls) were included in this study. Functional and structural MRI data were acquired to construct a WM functional network. Group differences in the global and regional topological characteristics were assessed by graph theory and the correlations with clinical and neuropsychological scores were analyzed. A support vector machine algorithm model was employed to classify individuals with IGE using WM functional connectivity as features, and the model's accuracy was evaluated using leave-one-out cross-validation. In IGE group, at the network level, the WM functional network exhibited increased assortativity; at the nodal level, 17 nodes presented nodal disturbances in WM functional network, and nodal disturbances of 11 nodes were correlated with cognitive performance scores, disease duration and age of onset. The classification model achieved the 72.6% accuracy, 0.746 area under the curve, 69.1% sensitivity, 76.2% specificity. Our study demonstrated that the WM functional network topological properties changes in childhood IGE, which were associated with cognitive function, and WM functional network may help clinical classification for childhood IGE. These findings provide novel information for understanding the pathogenesis of IGE and suggest that the WM function network might be qualified as potential biomarkers. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that trigger Tau aggregation in Alzheimer's disease (AD) remain elusive. Fungi, especially Saccharomyces cerevisiae (S. cerevisiae), can be found in brain samples from patients with AD. Here, we show that the yeast protein Ure2p from S. cerevisiae interacts with Tau and facilitates its aggregation. The Ure2p-seeded Tau fibrils are more potent in seeding Tau and causing neurotoxicity in vitro. When injected into the hippocampus of Tau P301S transgenic mice, the Ure2p-seeded Tau fibrils show enhanced seeding activity compared with pure Tau fibrils. Strikingly, intracranial injection of Ure2p fibrils promotes the aggregation of Tau and cognitive impairment in Tau P301S mice. Furthermore, intranasal infection of S. cerevisiae in the nasal cavity of Tau P301S mice accelerates the aggregation of Tau. Together, these observations indicate that the yeast protein Ure2p initiates Tau pathology. Our results provide a conceptual advance that non-mammalian prions may cross-seed mammalian prion-like proteins. [Display omitted] • Ure2p from S. cerevisiae trans -seeds Tau aggregation • Ure2p-seeded Tau fibrils are more toxic than control Tau fibrils • Intracerebral injection of Ure2p fibrils induces Tau pathology in Tau P301S mice • Intranasal inhalation of S. cerevisiae accelerates Tau pathology Meng et al. report that Ure2p from Saccharomyces cerevisiae interacts with Tau and facilitates its aggregation. Ure2p-seeded Tau fibrils induce Tau pathology and cognitive impairment. Thus, the trans -seeding of Tau by Ure2p promotes the onset and progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Recent studies indicated that the algal decomposition produces particulate and dissolved organic carbon (DOC), and can enhance denitrification in eutrophic lakes. However, the effects of the living cyanobacteria on nitrogen cycling in eutrophic lakes were still an unknown question. This study explores a new underlying mechanism of nitrate removal which is driven by living Microcystis . The results suggested that living Microcystis significantly enhanced the nitrate removal at sediment-water interface, with a nitrate removal rate of 0.54 d −1 , which was 2.57 times higher than the nitrate removal rate in the treatment without the addition of Microcystis . Measurements of Chl a and Fv/Fm confirmed that Microcystis was tolerant to the dark/anoxic condition, and the recovery experiments suggested that Microcystis could survive under such stress conditions for at least seven days. Meanwhile, DOC secreted by living Microcystis reached to 4.55 mg C mg −1 Chl a. These secretions were biodegradable hydrophilic and contained carbohydrates and proteins. Our study indicated that during blooms, sinking Microcystis cells could directly provide DOC as carbon source, then consequently enhanced the denitrification at sediment-water interface, and the interactive relationship between living cyanobacteria and permanent nitrate removal should be taken into account while studying nitrogen cycling in aquatic ecosystem. [ABSTRACT FROM AUTHOR]

Harmful cyanobacterial blooms (CyanoHABs) represent a serious threat to aquatic ecosystems. A beneficial use for these harmful microorganisms would be a promising resolution of this urgent issue. This study applied a simple method, nitrogen limitation, to cultivate cyanobacteria aimed at producing cyanobacterial carbon for denitrification. Under nitrogen-limited conditions, the common cyanobacterium, Microcystis, efficiently used nitrate, and had a higher intracellular C/N ratio. More importantly, organic carbons easily leached from its dry powder; these leachates were biodegradable and contained a larger amount of dissolved organic carbon (DOC) and carbohydrates, but a smaller amount of dissolved total nitrogen (DTN) and proteins. When applied to an anoxic system with a sediment-water interface, a significant increase of the specific NO X − -N removal rate was observed that was 14.2 times greater than that of the control. This study first suggests that nitrogen-limited cultivation is an efficient way to induce organic and carbohydrate accumulation in cyanobacteria, as well as a high C/N ratio, and that these cyanobacteria can act as a promising carbon source for denitrification. The results indicate that application as a carbon source is not only a new way to utilize cyanobacteria, but it also contributes to nitrogen removal in aquatic ecosystems, further limiting the proliferation of CyanoHABs. [ABSTRACT FROM AUTHOR]

Long-term l -DOPA treatment of Parkinson’s disease is accompanied with fluctuations of motor responses and l -DOPA-induced dyskinesia (LID). Phosphorylation of the dopamine and c-AMP regulated phosphoprotein of 32 kDa (DARPP-32) plays a role in the pathogenesis of LID, and thus dephosphorylation of this protein by activated calcineurin may help reduce LID. One important activator of calcineurin is the Ca 2+ ionophore ionomycin. Here, we investigated whether intrastriatal injection of ionomycin to hemiparkinsonian rats produced changes in l -DOPA responses including LID. We also analyzed the effects of ionomycin on key molecular mediators of LID. Results confirmed our hypothesis that ionomycin could downregulate the phosphorylation of DARPP32 at Thr-34 and reduce LID. Besides, ionomycin decreased two established molecular markers of LID, FosB/ΔFosB and phosphorylated ERK1/2. Ionomycin also decreased the phosphorylation of three main subunits of the NMDA receptor, NR1 phosphorylated at ser896, NR2A phosphorylated at Tyr-1325, and NR2B phosphorylated at Tyr-1472. Furthermore, the anti-LID effect of striatally injected ionomycin was not accompanied by reduction of the antiparkinsonian action of l -DOPA. These data indicate that ionomycin largely interacts with striatal mechanisms that are critical to the l -DOPA motor response highlighting the role of protein dephosphorylation by calcineurin. [ABSTRACT FROM AUTHOR]

Dopaminergic neurons loss in the substantia nigra (SN) and dopamine (DA) content loss in the striatum correlate well with disease severity in Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is a member of neurotrophin family and is necessary for the survival and development of DA neurons in the SN. Deficits in BDNF/TrkB receptors signaling contribute to the dysfunction of PD. Deoxygedunin, a derivative of gedunin produced from Indian neem tree, binds TrkB receptor and activates TrkB and its downstream signaling cascades in a BDNF-independent manner, and possesses neuroprotective effects in vitro and in vivo . In this study, we tested the neuroprotective effects of deoxygedunin in 6-hydroxydopamine (6-OHDA)-lesioned rat model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease. Rats were treated with deoxygedunin 5 mg/kg (i.p.) for one month started two weeks before 6-OHDA lesion (pre-treatment), or for two weeks right after lesion (post-treatment), with isovolumetric vehicle as control and normal. Mice were given deoxygedunin 5 mg/kg (i.p.) for 2 weeks and administrated with MPTP twice at the dose of 20 mg/kg (i.p.) on day 7. The results revealed that pretreatment with deoxygedunin improved PD models' behavioral performance and reduced dopaminergic neurons loss in SN, associated with the activation of TrkB receptors and its two major signaling cascades involving mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). Thus, our current study indicates that deoxygedunin, as a small molecule TrkB agonist, displays prominent neuroprotective properties, providing a novel therapeutic strategy for treating Parkinson's disease. [ABSTRACT FROM AUTHOR]

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM. • IAPP interacts with α-synuclein and accelerates its aggregation. • IAPP enhances the seeding activity and neurotoxicity of α-synuclein fibrils. • Administration of IAPP promotes α-synuclein pathology and PD-like phenotypes. [ABSTRACT FROM AUTHOR]

• AEP age-dependently cleaves γ-adducin at N357 in AD. • The AEP-generated γ-adducin (1-357) fragment translocates into nucleus and inhibits neurites growth. • γ-adducin (1-357) fragment induces neurites deficits and synaptic dysfunction by downregulating Rac2. • γ-adducin (1-357) fragment promotes AD-like pathology and cognitive impairments in vivo. Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD. [ABSTRACT FROM AUTHOR]