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Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory
Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer’s disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology
APP Processing Induced by Herpes Simplex Virus Type 1 (HSV-1) Yields Several APP Fragments in Human and Rat Neuronal Cells
Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During these episodes, newly produced virions may also reach the central nervous system (CNS), causing productive but generally asymptomatic infections. Epidemiological and experimental findings suggest that HSV-1 might contribute to the pathogenesis of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is related to an overproduction of amyloid beta (Aβ) and other neurotoxic peptides, which occurs during amyloidogenic endoproteolytic processing of the transmembrane amyloid precursor protein (APP). The aim of our study was to identify the effects of productive HSV-1 infection on APP processing in neuronal cells. We found that infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is followed by multiple cleavages of APP, which result in the intra- and/or extra-cellular accumulation of various neurotoxic species. These include: i) APP fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions of Aβ; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal APP-Fs; and iv) Aβ1-40 and Aβ1-42. Western blot analysis of infected-cell lysates treated with formic acid suggests that APP-F35 may be an Aβ oligomer. The multiple cleavages of APP that occur in infected cells are produced in part by known components of the amyloidogenic APP processing pathway, i.e., host-cell β-secretase, γ-secretase, and caspase-3-like enzymes. These findings demonstrate that HSV-1 infection of neuronal cells can generate multiple APP fragments with well-documented neurotoxic potentials. It is tempting to speculate that intra- and extracellular accumulation of these species in the CNS resulting from repeated HSV-1 reactivation could, in the presence of other risk factors, play a co-factorial role in the development of AD
Mitochondrial Bioenergetic Alterations in Mouse Neuroblastoma Cells Infected with Sindbis Virus: Implications to Viral Replication and Neuronal Death
The metabolic resources crucial for viral replication are provided by the host. Details of the mechanisms by which viruses interact with host metabolism, altering and recruiting high free-energy molecules for their own replication, remain unknown. Sindbis virus, the prototype of and most widespread alphavirus, causes outbreaks of arthritis in humans and serves as a model for the study of the pathogenesis of neurological diseases induced by alphaviruses in mice. In this work, respirometric analysis was used to evaluate the effects of Sindbis virus infection on mitochondrial bioenergetics of a mouse neuroblastoma cell lineage, Neuro 2a. The modulation of mitochondrial functions affected cellular ATP content and this was synchronous with Sindbis virus replication cycle and cell death. At 15 h, irrespective of effects on cell viability, viral replication induced a decrease in oxygen consumption uncoupled to ATP synthesis and a 36% decrease in maximum uncoupled respiration, which led to an increase of 30% in the fraction of oxygen consumption used for ATP synthesis. Decreased proton leak associated to complex I respiration contributed to the apparent improvement of mitochondrial function. Cellular ATP content was not affected by infection. After 24 h, mitochondria dysfunction was clearly observed as maximum uncoupled respiration reduced 65%, along with a decrease in the fraction of oxygen consumption used for ATP synthesis. Suppressed respiration driven by complexes I- and II-related substrates seemed to play a role in mitochondrial dysfunction. Despite the increase in glucose uptake and glycolytic flux, these changes were followed by a 30% decrease in ATP content and neuronal death. Taken together, mitochondrial bioenergetics is modulated during Sindbis virus infection in such a way as to favor ATP synthesis required to support active viral replication. These early changes in metabolism of Neuro 2a cells may form the molecular basis of neuronal dysfunction and Sindbis virus-induced encephalitis
Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models
Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression
Sugarcane (Saccharum X officinarum): A Reference Study for the Regulation of Genetically Modified Cultivars in Brazil
Global interest in sugarcane has increased significantly in recent years due to its economic impact on sustainable energy production. Sugarcane breeding and better agronomic practices have contributed to a huge increase in sugarcane yield in the last 30Â years. Additional increases in sugarcane yield are expected to result from the use of biotechnology tools in the near future. Genetically modified (GM) sugarcane that incorporates genes to increase resistance to biotic and abiotic stresses could play a major role in achieving this goal. However, to bring GM sugarcane to the market, it is necessary to follow a regulatory process that will evaluate the environmental and health impacts of this crop. The regulatory review process is usually accomplished through a comparison of the biology and composition of the GM cultivar and a non-GM counterpart. This review intends to provide information on non-GM sugarcane biology, genetics, breeding, agronomic management, processing, products and byproducts, as well as the current technologies used to develop GM sugarcane, with the aim of assisting regulators in the decision-making process regarding the commercial release of GM sugarcane cultivars
Sensitivity projections for a dual-phase argon TPC optimized for light dark matter searches through the ionization channel
Dark matter lighter than 10 GeV/c encompasses a promising range of
candidates. A conceptual design for a new detector, DarkSide-LowMass, is
presented, based on the DarkSide-50 detector and progress toward DarkSide-20k,
optimized for a low-threshold electron-counting measurement. Sensitivity to
light dark matter is explored for various potential energy thresholds and
background rates. These studies show that DarkSide-LowMass can achieve
sensitivity to light dark matter down to the solar neutrino floor for GeV-scale
masses and significant sensitivity down to 10 MeV/c considering the Migdal
effect or interactions with electrons. Requirements for optimizing the
detector's sensitivity are explored, as are potential sensitivity gains from
modeling and mitigating spurious electron backgrounds that may dominate the
signal at the lowest energies
Study on cosmogenic activation above ground for the DarkSide-20k project
The activation of materials due to the exposure to cosmic rays may become an
important background source for experiments investigating rare event phenomena.
DarkSide-20k is a direct detection experiment for galactic dark matter
particles, using a two-phase liquid argon time projection chamber filled with
49.7 tonnes (active mass) of Underground Argon (UAr) depleted in 39Ar. Here,
the cosmogenic activity of relevant long-lived radioisotopes induced in the
argon and other massive components of the set-up has been estimated; production
of 120 t of radiopure UAr is foreseen. The expected exposure above ground and
production rates, either measured or calculated, have been considered. From the
simulated counting rates in the detector due to cosmogenic isotopes, it is
concluded that activation in copper and stainless steel is not problematic.
Activation of titanium, considered in early designs but not used in the final
design, is discussed. The activity of 39Ar induced during extraction,
purification and transport on surface, in baseline conditions, is evaluated to
be 2.8% of the activity measured in UAr from the same source, and thus
considered acceptable. Other products in the UAr such as 37Ar and 3H are shown
to not be relevant due to short half-life and assumed purification methods
Directionality of nuclear recoils in a liquid argon time projection chamber
The direct search for dark matter in the form of weakly interacting massive
particles (WIMP) is performed by detecting nuclear recoils (NR) produced in a
target material from the WIMP elastic scattering. A promising experimental
strategy for direct dark matter search employs argon dual-phase time projection
chambers (TPC). One of the advantages of the TPC is the capability to detect
both the scintillation and charge signals produced by NRs. Furthermore, the
existence of a drift electric field in the TPC breaks the rotational symmetry:
the angle between the drift field and the momentum of the recoiling nucleus can
potentially affect the charge recombination probability in liquid argon and
then the relative balance between the two signal channels. This fact could make
the detector sensitive to the directionality of the WIMP-induced signal,
enabling unmistakable annual and daily modulation signatures for future
searches aiming for discovery. The Recoil Directionality (ReD) experiment was
designed to probe for such directional sensitivity. The TPC of ReD was
irradiated with neutrons at the INFN Laboratori Nazionali del Sud, and data
were taken with 72 keV NRs of known recoil directions. The direction-dependent
liquid argon charge recombination model by Cataudella et al. was adopted and a
likelihood statistical analysis was performed, which gave no indications of
significant dependence of the detector response to the recoil direction. The
aspect ratio R of the initial ionization cloud is estimated to be 1.037 +/-
0.027 and the upper limit is R < 1.072 with 90% confidence levelComment: 20 pages, 10 figures, submitted to Eur. Phys. J.
EXCESSIVE WEIGHT – MUSCLE DEPLETION PARADOX AND CARDIOVASCULAR RISK FACTORS IN OUTPATIENTS WITH INFLAMMATORY BOWEL DISEASE
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