The emergence of the H7N9 influenza virus in humans in Eastern China has raised concerns that a new influenza pandemic could occur. Here, we used a ferret model to evaluate the infectivity and ...transmissibility of A/Shanghai/2/2013 (SH2), a human H7N9 virus isolate. This virus replicated in the upper and lower respiratory tracts of the ferrets and was shed at high titers for 6 to 7 days, with ferrets showing relatively mild clinical signs. SH2 was efficiently transmitted between ferrets via direct contact, but less efficiently by airborne exposure. Pigs were productively infected by SH2 and shed virus for 6 days but were unable to transmit the virus to naïve pigs or ferrets. Under appropriate conditions, human-to-human transmission of the H7N9 virus may be possible.
Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and ...molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX-2 represents a mechanism-based target for HCC prevention.
The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. ...However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.
The emerging paradigm of 'abundant-data' computing requires real-time analytics on enormous quantities of data collected by a mushrooming network of sensors. Todays computing technology, however, ...cannot scale to satisfy such big data applications with the required throughput and energy efficiency. The next technology frontier will be monolithically integrated chips with three-dimensionally interleaved memory and logic for unprecedented data bandwidth with reduced energy consumption. In this work, we exploit the atomically thin nature of the graphene edge to assemble a resistive memory (∼ 3 Å thick) stacked in a vertical three-dimensional structure. We report some of the lowest power and energy consumption among the emerging non-volatile memories due to an extremely thin electrode with unique properties, low programming voltages, and low current. Circuit analysis of the three-dimensional architecture using experimentally measured device properties show higher storage potential for graphene devices compared that of metal based devices.
Multiferroics, where (anti-) ferromagnetic, ferroelectric and ferroelastic order parameters coexist, enable manipulation of magnetic ordering by an electric field through switching of the electric ...polarization. It has been shown that realization of magnetoelectric coupling in a single-phase multiferroic such as BiFeO3 requires ferroelastic (71 , 109 ) rather than ferroelectric (180 ) domain switching. However, the control of such ferroelastic switching in a single-phase system has been a significant challenge as elastic interactions tend to destabilize small switched volumes, resulting in subsequent ferroelastic back-switching at zero electric field, and thus the disappearance of non-volatile information storage. Guided by our phase-field simulations, here we report an approach to stabilize ferroelastic switching by eliminating the stress-induced instability responsible for back-switching using isolated monodomain BiFeO3 islands. This work demonstrates a critical step to control and use non-volatile magnetoelectric coupling at the nanoscale. Beyond magnetoelectric coupling, it provides a framework for exploring a route to control multiple order parameters coupled to ferroelastic order in other low-symmetry materials.
The use of heart rate variability (HRV) in research has been greatly popularized over the past decades due to the ease and affordability of HRV collection, coupled with its clinical relevance and ...significant relationships with psychophysiological constructs and psychopathological disorders. Despite the wide use of electrocardiograms (ECG) in research and advancements in sensor technology, the analytical approach and steps applied to obtain HRV measures can be seen as complex. Thus, this poses a challenge to users who may not have the adequate background knowledge to obtain the HRV indices reliably. To maximize the impact of HRV-related research and its reproducibility, parallel advances in users' understanding of the indices and the standardization of analysis pipelines in its utility will be crucial. This paper addresses this gap and aims to provide an overview of the most up-to-date and commonly used HRV indices, as well as common research areas in which these indices have proven to be very useful, particularly in psychology. In addition, we also provide a step-by-step guide on how to perform HRV analysis using an integrative neurophysiological toolkit, NeuroKit2.
Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using ...FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo.
Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI ...misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.
Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity ...regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 x 10⁻²⁵), rs495828 (P=3.5 x 10⁻⁸) and rs8176746 (P=9.3 x 10⁻⁵) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.
Giant Piezoelectricity on Si for Hyperactive MEMS Baek, S. H.; Park, J.; Kim, D. M. ...
Science (American Association for the Advancement of Science),
11/2011, Letnik:
334, Številka:
6058
Journal Article
Recenzirano
Microelectromechanical systems (MEMS) incorporating active piezoelectric layers offer integrated actuation, sensing, and transduction. The broad implementation of such active MEMS has long been ...constrained by the inability to integrate materials with giant piezoelectric response, such as Pb(MG 1/3 Nb 2/3 )O₃-PbTiO₃ (PMN-PT). We synthesized high-quality PMN-PT epitaxial thin films on vicinal (001) Si wafers with the use of an epitaxial (001) SrTiO₃ template layer with superior piezoelectric coefficients (e 31,f = -27 ± 3 coulombs per square meter) and figures of merit for piezoelectric energy-harvesting systems. We have incorporated these heterostructures into microcantilevers that are actuated with extremely low drive voltage due to thin-film piezoelectric properties that rival bulk PMN-PT single crystals. These epitaxial heterostructures exhibit very large electromechanical coupling for ultrasound medical imaging, microfluidic control, mechanical sensing, and energy harvesting.
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