Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have ...failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.
Modulation of voltage-gated sodium channels (VGSC) can have a major impact on cell excitability. Analysis of calmodulin (CaM) binding to GST-fusion proteins containing the C-terminal domains of ...Nav1.1-Nav1.9 indicates that some of the tetrodotoxin-sensitive VGSC isoforms, including NaV1.4 and NaV1.6, are able to bind CaM in a calcium-independent manner. Here we demonstrate that association with CaM is important for functional expression of NaV1.4 and NaV1.6 VGSCs. Disrupting the interaction between CaM and the C terminus of NaV1.4 and NaV1.6 channels reduced current amplitude by 99 and 62%, respectively. Overexpression of CaM increased the current generated by Nav1.4 and Nav1.6 C-terminal mutant constructs that exhibited intermediate current densities and intermediate binding affinities for CaM, demonstrating that this effect on current density was directly dependent on the ability of the C terminus to bind CaM. In addition to the effects on current density, calmodulin also was able to modulate the inactivation kinetics of Nav1.6, but not Nav1.4, currents in a calcium-dependent manner. Our data demonstrate that CaM can regulate the properties of VGSCs via calcium-dependent and calcium-independent mechanisms and suggest that modulation of neuronal sodium channels may play a role in calcium-dependent neuronal plasticity.
Abstract
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. IL-1β produced by macrophages and neutrophils drives gouty flares that ...cause joint destruction, intense pain and fever. Small clinical trials have reported that IL-1R antagonists reduced pain in gout patients, but these biologicals are expensive and may compromise immune responses. Moreover, current treatment strategies for gout are limited in efficacy and do not specifically target the NLRP3 inflammasome. NLRP3 activation is regulated by numerous metabolic byproducts. However, metabolites that impact neutrophil inflammasome remain unknown. We identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune-defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal activated macrophages which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in outbred rats fed a ketogenic diet, BHB blocked NLRP3-dependent IL-1β secretion from neutrophils from both mice and humans, irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel is also an anti-inflammatory molecule that may serve as a treatment for gout.
Elementary Duality of Modules Herzog, Ivo
Transactions of the American Mathematical Society,
1993, Letnik:
340, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Let R be a ring. A formula φ(x) in the language of left R-modules is called a positive primitive formula (ppf) if it is of the form$\exists\mathbf{y}(AB)\binom{x}{y} = \mathbf{0}$where A and B are ...matrices of appropriate size with entries in R. We apply Prest's notion of Dφ(x), the ppf in the language of right R-modules dual to φ, to show that the model theory of left R-modules as developed by Ziegler Z is in some sense dual to the model theory of right R-modules. We prove that the topologies on the left and right Ziegler spectra are "isomorphic" (Proposition 4.4). When the lattice of ppfs is well behaved, there is a homeomorphism D between the left and right Ziegler spectra which assigns to a given pure-injective indecomposable left R-module U the dual pure-injective indecomposable right R-module DU. Theorem 6.6 asserts that given a complete theory T of left R-modules, there is a dual complete theory DT of right R-modules with corresponding Baur-Garavaglia-Monk invariants. In the end, we give some conditions on a pure-injective indecomposableRUwhich ensure that its dual DU may be represented as a$\hom$set of the form$\operatorname{Hom}_S(_RU_S, E_S)$where S is some ring makingRU
Sinto a bimodule and ESis injective.
To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain ...antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-A.sup.g7 and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-A.sup.g7, which activated autoreactive CD4.sup.+ T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-A.sup.g7 RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-A.sup.g7 RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries.
Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies. ^sup 1^H NMR has been a popular technique to detect several dozen metabolites ...in blood plasma. In order for ^sup 1^H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted ^sup 1^H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite ^sup 1^H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 min or 15 % per sample allowed the acquisition of a ^sup 1^H NMR spectrum with high diffusion weighting. The metabolite ^sup 1^H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative ^sup 1^H NMR of human plasma.
Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies.
H NMR has been a popular technique to detect several dozen metabolites in ...blood plasma. In order for
H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted
H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite
H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 minutes or 15% per sample allowed the acquisition of a
H NMR spectrum with high diffusion weighting. The metabolite
H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative
H NMR of human plasma.
The conflict about the fragments of "Apologia or Defense for the Rational Reverers of God" by the Hamburg scholar Hermann Samuel Reimarus and theCounter-propositionsby Gotthold Ephraim Lessing caused ...an uproar in the Lutheran theological world of the 18th century. Would this form of Christianity, rooted in the tradition of the Lutheran Reformation, be superseded by the Enlightenment if literary, historical and religious-philosophical criticism of the Bible were now allowed? Lessing presents his solution of the problem inAxioms, which this book places in the context of his overall thought.
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