Major depressive disorder (MDD), anxiety disorders (ANX), and chronic pain (CP) are closely-related disorders with both high degrees of comorbidity among them and shared risk factors. Considering ...this multi-level overlap, but also the distinct phenotypes of the disorders, we hypothesized both common and disorder-specific changes of large-scale brain systems, which mediate neural mechanisms and impaired behavioral traits, in MDD, ANX, and CP. To identify such common and disorder-specific brain changes, we conducted a transdiagnostic, multimodal meta-analysis of structural and functional MRI-studies investigating changes of gray matter volume (GMV) and intrinsic functional connectivity (iFC) of large-scale intrinsic brain networks across MDD, ANX, and CP. The study was preregistered at PROSPERO (CRD42019119709). 320 studies comprising 10,931 patients and 11,135 healthy controls were included. Across disorders, common changes focused on GMV-decrease in insular and medial-prefrontal cortices, located mainly within the so-called default-mode and salience networks. Disorder-specific changes comprised hyperconnectivity between default-mode and frontoparietal networks and hypoconnectivity between limbic and salience networks in MDD; limbic network hyperconnectivity and GMV-decrease in insular and medial-temporal cortices in ANX; and hypoconnectivity between salience and default-mode networks and GMV-increase in medial temporal lobes in CP. Common changes suggested a neural correlate for comorbidity and possibly shared neuro-behavioral chronification mechanisms. Disorder-specific changes might underlie distinct phenotypes and possibly additional disorder-specific mechanisms.
Inclusion body myositis (IBM) is a chronic, mostly treatment-resistant, inflammatory myopathy with a pathology that centers around specific interactions between inflammation and protein accumulation. ...The study aimed to identify the inflammasome as a key event in the complex network of pathomechanisms. Regulation of the inflammasome was assessed in a well-established pro-inflammatory cell culture model using human myoblasts and primary human myotubes. By quantitative PCR, western blot and immunocytochemistry, inflammasome markers including NLRP3 were assessed in muscle cells exposed to the cytokines IL-1β and IFN-γ. The data were corroborated by analysis of muscle biopsies from patients with IBM compared to other myositis subtypes. In the cell culture model of IBM, the NLRP3 inflammasome was significantly overexpressed, as evidenced by western blot (
= 0.03) and quantitative PCR (
< 0.01). Target genes that play a role in inflammasome assembly, T-cell migration, and MHC-I expression (
= 0.009) were highly co-upregulated. NLRP3 was significantly overexpressed in muscle biopsies from IBM samples compared to disease controls (
= 0.049), including other inflammatory myopathies. Due to the extraordinary features of the pathogenesis and the pronounced upregulation of NLRP3 in IBM, the inflammasome could serve as a key molecule that drives the inflammatory cascade as well as protein accumulation in the muscle. These data can be useful for future therapeutic developments.
Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological ...findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19.
A retrospective analysis was performed on 55 COVID-19 patients classified as mild (
= 22), moderate (
= 25), and severe (
= 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF.
Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis.
Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.
Use of laparotomy sponges to protect abdominal viscera during gastrointestinal surgery is described in nonspecific terms by various sources, but no definitive guidelines have been established in ...veterinary literature. The objective of this study was to compare the in vitro efficacy of various layer-densities of laparotomy sponges at reducing bacterial contamination from multiple contaminant volumes during multiple exposure times. A standardized Escherichia coli inoculum water solution was applied over sterile laparotomy sponges overlying blood agar plates. Four laparotomy sponge layer-densities, 4 volumes of E. coli inoculum water solution, and 4 exposure times were evaluated. All blood agar plates were incubated for 48 hours followed by surface area measurements of colonization of each blood agar plate at 24 and 48 hours. The procedure was repeated thrice. Bacterial colonization occurred on 100% (192/192) of inoculated blood agar plates. There was a statistically significant decrease in colonized area with increasing layer-density of laparotomy sponges (P<0.0001). Comparison between the layer-density of sponges were statistically significant in resulting infected area (P<0.01), except comparison between 6- and 8-layers (P = 0.9490). Colonized area was not significantly altered by time of exposure. Results suggested that increasing the layer-density of laparotomy sponges has significant effect on reducing strikethrough bacterial colonization in an in vitro model. The results of this study can be used when performing gastrointestinal surgery to help guide laparotomy sponge use to reduce peritoneal bacterial contamination.
Against the backdrop of global change, the intensity, duration, and frequency of droughts are projected to increase and threaten forest ecosystems worldwide. Tree responses to drought are complex and ...likely to vary among species, drought characteristics, and site conditions. Here, we examined the drought response patterns of three major temperate tree species, s. fir (Abies alba), E. beech (Fagus sylvatica), and N. spruce (Picea abies), along an ecological gradient in the South – Central – East part of Germany that included a total of 37 sites with varying climatic and soil conditions. We relied on annual tree-ring data to assess the influence of different drought characteristics and (micro-) site conditions on components of tree resilience and to detect associated temporal changes. Our study revealed that nutrient regime, drought frequency, and hydraulic conditions in the previous and subsequent years were the main determinants of drought responses, with pronounced differences among species. Specifically, we found that (a) higher drought frequency was associated with higher resistance and resilience for N. spruce and E. beech; (b) more favorable climatic conditions in the two preceding and following years increased drought resilience and determined recovery potential of E. beech after extreme drought; (c) a site's nutrient regime, rather than micro-site differences in water availability, determined drought responses, with trees growing on sites with a balanced nutrient regime having a higher capacity to withstand extreme drought stress; (d) E. beech and N. spruce experienced a long-term decline in resilience. Our results indicate that trees under extreme drought stress benefit from a balanced nutrient supply and highlight the relevance of water availability immediately after droughts. Observed long-term trends confirm that N. spruce is suffering from persistent climatic changes, while s. fir is coping better. These findings might be especially relevant for monitoring, scenario analyses, and forest ecosystem management.
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•Drought response analyses of fir, beech, and spruce along an ecological gradient•Balanced nutrient regime was beneficial under extreme droughts.•Beneficial post-drought climatic conditions facilitated recovery potential of beech.•Recurrent droughts were not associated with reduced resilience.•Beech and spruce showed a long-term decline in drought resilience.
We study model theory of fields with actions of a fixed finite group scheme. We prove the existence and simplicity of a model companion of the theory of such actions, which generalizes our previous ...results about truncated iterative Hasse–Schmidt derivations 13 and about Galois actions 14. As an application of our methods, we obtain a new model complete theory of actions of a finite group on fields of finite imperfection degree.
Abstract Introduction Fibroblast activation protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial ...infarction (MI) and potential effects on cardiac wound healing are largely unknown. Methods MI was induced in rats and FAP expression was analyzed at 3, 7 and 28 days post-MI by microarray, Western blot and immunohistochemistry. In human hearts after MI, a FAP+ fibroblast population was identified, and characterized by immunohistochemistry for prolyl-4-hydroxylase β, α-smooth muscle actin, Thy-1 and vimentin. Signaling pathways leading to FAP expression were studied in human cardiac fibroblasts by Western blot and ELISA using TGFβ1 , TGF-beta type I-receptor (TGFbR1)-inhibitor SB431542 or the MAPK-inhibitor U0126 as well as siRNA targeting SMAD2 and SMAD3. Finally, fibroblasts were assayed for FAP-dependent migration (modified Boyden-chamber), proliferation (BrdU-assay) and gelatinolytic activity by gelatin zymography. Results In rats, FAP expression was increased after MI especially in the peri-infarct area peaking at 7 days post-MI. Co-localization analysis identified the majority of FAP+ cells as activated proto-myofibroblasts and myofibroblasts. Concordantly, FAP+ fibroblasts were abundant in ischemic tissue of human hearts after MI, but not in healthy control hearts. In vitro, FAP was induced by TGFβ1 via the canonical SMAD2/SMAD3 pathway. Depletion of FAP in fibroblasts reduced migratory capacity, while proliferation was not affected. Gelatin zymography revealed gelatinase activity by fibroblast-derived FAP. Conclusion In this study, we show for the first time the expression of FAP in activated fibroblasts after MI and its activation by TGFβ1 . Effects of FAP on fibroblast migration and gelatinolytic activity indicate a potential role in cardiac wound healing and remodeling.
Herein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative ...carbonylation approach for isotope labeling with near stoichiometric, ex situ generated 12C, or 13C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2 liberated during decarboxylation has also been developed as a proof‐of‐concept approach that CO2‐derived compounds can be converted to CO‐containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low‐pressure carbonylation methodologies, along with rational for the development of future methodologies.
Herein, an oxygen atom deletion strategy via sequential Pd‐catalyzed decarboxylative carbonylation of carbonates and carbamates to afford esters and amides is reported. Operating under low pressures (near stoichiometric or substoichiometric), either 13C labeled products are accessed or a proof‐of‐concept that CO2 formed upon decarboxylation can be reduced in situ and reincorporated as CO is shown.
We have performed a systematic study of the entropy term in the MM/GBSA (molecular mechanics combined with generalized Born and surface-area solvation) approach to calculate ligand-binding ...affinities. The entropies are calculated by a normal-mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with distances larger than 8–16 Å to the ligand, including a 4 Å shell of fixed protein residues and water molecules, change the absolute entropies by 1–5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7–1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the whole protein within statistical uncertainty (1–2 kJ/mol). We have also tested to use a distance-dependent dielectric constant in the minimization and frequency calculation (ε = 4r), but it typically gives slightly different entropies and poorer binding affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 Å) and ε =1. Such an approach also gives an improved precision for the calculated binding free energies.
This study investigated characteristic large-scale brain changes in schizophrenia. Numerous imaging studies have demonstrated brain changes in schizophrenia, particularly aberrant intrinsic ...functional connectivity (iFC) of ongoing brain activity, measured by resting-state functional magnetic resonance imaging, and aberrant gray matter volume (GMV) of distributed brain regions, measured by structural magnetic resonance imaging. It is unclear, however, which iFC changes are specific to schizophrenia compared with those of other disorders and whether such specific iFC changes converge with GMV changes. To address this question of specific substantial dysconnectivity in schizophrenia, we performed a transdiagnostic multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies in schizophrenia and other psychiatric disorders.
Multiple databases were searched up to June 2017 for whole-brain seed-based iFC studies and voxel-based morphometry studies in schizophrenia, major depressive disorder, bipolar disorder, addiction, and anxiety. Coordinate-based meta-analyses were performed to detect 1) schizophrenia-specific hyperconnectivity or hypoconnectivity of intrinsic brain networks (compared with hyperconnectivity or hypoconnectivity of each other disorder both separately and combined across comparisons) and 2) the overlap between dysconnectivity and GMV changes (via multimodal conjunction analysis).
For iFC meta-analysis, 173 publications comprising 4962 patients and 4575 control subjects were included, and for GMV meta-analysis, 127 publications comprising 6311 patients and 6745 control subjects were included. Disorder-specific iFC dysconnectivity in schizophrenia (consistent across comparisons with other disorders) was found for limbic, frontoparietal executive, default mode, and salience networks. Disorder-specific dysconnectivity and GMV reductions converged in insula, lateral postcentral cortex, striatum, and thalamus.
Results demonstrated specific substantial dysconnectivity in schizophrenia in insula, lateral postcentral cortex, striatum, and thalamus. Data suggest that these regions are characteristic targets of schizophrenia.
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