In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases

<p>Abstract</p> <p>Background</p> <p>CHI3L1 (YKL-40) is up-regulated in a variety of inflammatory conditions and cancers. We have previously reported elevated CHI3L1 concentration in the cerebrospinal fluid (CSF) of human and non-human primates with lentiviral encephalitis and using immunohistochemistry showed that CHI3L1 was associated with astrocytes.</p> <p>Methods</p> <p>In the current study CHI3L1 transcription and expression were evaluated in a variety of acute and chronic human neurological diseases.</p> <p>Results</p> <p>ELISA revealed significant elevation of CHI3L1 in the CSF of multiple sclerosis (MS) patients as well as mild elevation with aging. <it>In situ </it>hybridization (ISH) showed CHI3L1 transcription mostly associated with reactive astrocytes, that was more pronounced in inflammatory conditions like lentiviral encephalitis and MS. Comparison of CHI3L1 expression in different stages of brain infarction showed that YKL40 was abundantly expressed in astrocytes during acute phases and diminished to low levels in chronic infarcts.</p> <p>Conclusions</p> <p>Taken together, these findings demonstrate that CHI3L1 is induced in astrocytes in a variety of neurological diseases but that it is most abundantly associated with astrocytes in regions of inflammatory cells.</p

Expanded Diversity and Phylogeny of mer Genes Broadens Mercury Resistance Paradigms and Reveals an Origin for MerA Among Thermophilic Archaea

Mercury (Hg) is a highly toxic element due to its high affinity for protein sulfhydryl groups, which upon binding, can destabilize protein structure and decrease enzyme activity. Prokaryotes have evolved enzymatic mechanisms to detoxify inorganic Hg and organic Hg (e.g., MeHg) through the activities of mercuric reductase (MerA) and organomercury lyase (MerB), respectively. Here, the taxonomic distribution and evolution of MerAB was examined in 84,032 archaeal and bacterial genomes, metagenome assembled genomes, and single-cell genomes. Homologs of MerA and MerB were identified in 7.8 and 2.1% percent of genomes, respectively. MerA was identified in the genomes of 10 archaeal and 28 bacterial phyla previously unknown to code for this functionality. Likewise, MerB was identified in 2 archaeal and 11 bacterial phyla previously unknown to encode this functionality. Surprisingly, homologs of MerB were identified in a number of genomes (∼50% of all MerB-encoding genomes) that did not encode MerA, suggesting alternative mechanisms to detoxify Hg(II) once it is generated in the cytoplasm. Phylogenetic reconstruction of MerA place its origin in thermophilic Thermoprotei (Crenarchaeota), consistent with high levels of Hg(II) in geothermal environments, the natural habitat of this archaeal class. MerB appears to have been recruited to the mer operon relatively recently and likely among a mesophilic ancestor of Euryarchaeota and Thaumarchaeota. This is consistent with the functional dependence of MerB on MerA and the widespread distribution of mesophilic microorganisms that methylate Hg(II) at lower temperature. Collectively, these results expand the taxonomic and ecological distribution of mer-encoded functionalities, and suggest that selection for Hg(II) and MeHg detoxification is dependent not only on the availability and type of mercury compounds in the environment but also the physiological potential of the microbes who inhabit these environments. The expanded diversity and environmental distribution of MerAB identify new targets to prioritize for future research

Weak values of a quantum observable and the cross-Wigner distribution

We study the weak values of a quantum observable from the point of view of the Wigner formalism. The main actor is here the cross-Wigner transform of two functions, which is in disguise the cross-ambiguity function familiar from radar theory and time-frequency analysis. It allows us to express weak values using a complex probability distribution. We suggest that our approach seems to confirm that the weak value of an observable is, as conjectured by several authors, due to the interference of two wavefunctions, one coming from the past, and the other from the future.Comment: Submitted for publicatio

Exploratory Behavior, Trap Models and Glass Transitions

A random walk is performed on a disordered landscape composed of $N$ sites randomly and uniformly distributed inside a $d$-dimensional hypercube. The walker hops from one site to another with probability proportional to $\exp [- \beta E(D)]$, where $\beta = 1/T$ is the inverse of a formal temperature and $E(D)$ is an arbitrary cost function which depends on the hop distance $D$. Analytic results indicate that, if $E(D) = D^{d}$ and $N \to \infty$, there exists a glass transition at $\beta_d = \pi^{d/2}/\Gamma(d/2 + 1)$. Below $T_d$, the average trapping time diverges and the system falls into an out-of-equilibrium regime with aging phenomena. A L\'evy flight scenario and applications to exploratory behavior are considered.Comment: 4 pages, 1 figure, new versio

Cerebrospinal fluid levels of glial marker YKL-40 strongly associated with axonal injury in HIV infection

Background: HIV-1 infects the central nervous system (CNS) shortly after transmission. This leads to a chronic intrathecal immune activation. YKL-40, a biomarker that mainly reflects activation of astroglial cells, has not been thoroughly investigated in relation to HIV. The objective of our study was to characterize cerebrospinal fluid (CSF) YKL-40 in chronic HIV infection, with and without antiretroviral treatment (ART). Methods: YKL-40, neopterin, and the axonal marker neurofilament light protein (NFL) were analyzed with ELISA in archived CSF samples from 120 HIV-infected individuals (85 untreated neuroasymptomatic patients, 7 with HIVassociated dementia, and 28 on effective ART) and 39 HIV-negative controls. Results: CSF YKL-40 was significantly higher in patients with HIV-associated dementia compared to all other groups. It was also higher in untreated neuroasymptomatic individuals with CD4 cell count < 350 compared to controls. Significant correlations were found between CSF YKL-40 and age (r = 0.38, p < 0.001), CD4 (r = − 0.36, p < 0. 001), plasma HIV RNA (r = 0.35, p < 0.001), CSF HIV RNA (r = 0.35, p < 0.001), CSF neopterin (r = 0.40, p < 0.001), albumin ratio (r = 0.44, p < 0.001), and CSF NFL (r = 0.71, p < 0.001). Age, CD4 cell count, albumin ratio, and CSF HIV RNA were found as independent predictors of CSF YKL-40 concentrations in multivariable analysis. In addition, CSF YKL-40 was revealed as a strong independent predictor of CSF NFL together with age, CSF neopterin, and CD4 cell count. Conclusions: CSF YKL-40 is a promising biomarker candidate for understanding the pathogenesis of HIV in the CNS. The strong correlation between CSF YKL-40 and NFL suggests a pathogenic association between astroglial activation and axonal injury, and implies its utility in assessing the prognostic value of YKL-40

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Dietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders. Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil–DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfusion in an animal model. Ung+/+ and Ung−/− mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung−/− FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung+/+ FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung−/− hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don’t lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion or UNG deficiency is required

Characterization of the Metabolically Modified Heavy Metal-Resistant Cupriavidus metallidurans Strain MSR33 Generated for Mercury Bioremediation

BACKGROUND: Mercury-polluted environments are often contaminated with other heavy metals. Therefore, bacteria with resistance to several heavy metals may be useful for bioremediation. Cupriavidus metallidurans CH34 is a model heavy metal-resistant bacterium, but possesses a low resistance to mercury compounds. METHODOLOGY/PRINCIPAL FINDINGS: To improve inorganic and organic mercury resistance of strain CH34, the IncP-1β plasmid pTP6 that provides novel merB, merG genes and additional other mer genes was introduced into the bacterium by biparental mating. The transconjugant Cupriavidus metallidurans strain MSR33 was genetically and biochemically characterized. Strain MSR33 maintained stably the plasmid pTP6 over 70 generations under non-selective conditions. The organomercurial lyase protein MerB and the mercuric reductase MerA of strain MSR33 were synthesized in presence of Hg(2+). The minimum inhibitory concentrations (mM) for strain MSR33 were: Hg(2+), 0.12 and CH(3)Hg(+), 0.08. The addition of Hg(2+) (0.04 mM) at exponential phase had not an effect on the growth rate of strain MSR33. In contrast, after Hg(2+) addition at exponential phase the parental strain CH34 showed an immediate cessation of cell growth. During exposure to Hg(2+) no effects in the morphology of MSR33 cells were observed, whereas CH34 cells exposed to Hg(2+) showed a fuzzy outer membrane. Bioremediation with strain MSR33 of two mercury-contaminated aqueous solutions was evaluated. Hg(2+) (0.10 and 0.15 mM) was completely volatilized by strain MSR33 from the polluted waters in presence of thioglycolate (5 mM) after 2 h. CONCLUSIONS/SIGNIFICANCE: A broad-spectrum mercury-resistant strain MSR33 was generated by incorporation of plasmid pTP6 that was directly isolated from the environment into C. metallidurans CH34. Strain MSR33 is capable to remove mercury from polluted waters. This is the first study to use an IncP-1β plasmid directly isolated from the environment, to generate a novel and stable bacterial strain useful for mercury bioremediation

High methylmercury in Arctic and subarctic ponds is related to nutrient levels in the warming eastern Canadian Arctic

Permafrost thaw ponds are ubiquitous in the eastern Canadian Arctic, yet little information exists on their potential as sources of methylmercury (MeHg) to freshwaters. They are microbially active and conducive to methylation of inorganic mercury, and are also affected by Arctic warming. This multiyear study investigated thaw ponds in a discontinuous permafrost region in the Subarctic taiga (Kuujjuarapik-Whapmagoostui, QC) and a continuous permafrost region in the Arctic tundra (Bylot Island, NU). MeHg concentrations in thaw ponds were well above levels measured in most freshwater ecosystems in the Canadian Arctic (>0.1 ng L−1). On Bylot, ice-wedge trough ponds showed significantly higher MeHg (0.3−2.2 ng L−1) than polygonal ponds (0.1−0.3 ng L−1) or lakes (<0.1 ng L−1). High MeHg was measured in the bottom waters of Subarctic thaw ponds near Kuujjuarapik (0.1−3.1 ng L−1). High water MeHg concentrations in thaw ponds were strongly correlated with variables associated with high inputs of organic matter (DOC, a320, Fe), nutrients (TP, TN), and microbial activity (dissolved CO2 and CH4). Thawing permafrost due to Arctic warming will continue to release nutrients and organic carbon into these systems and increase ponding in some regions, likely stimulating higher water concentrations of MeHg. Greater hydrological connectivity from permafrost thawing may potentially increase transport of MeHg from thaw ponds to neighboring aquatic ecosystems