Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as ...the cells responsible for the progression of the fibrotic process, and they originate from several sources, including quiescent tissue fibroblasts, circulating CD34⁺ fibrocytes and the phenotypic conversion of various cell types into activated myofibroblasts. Several studies have demonstrated that endothelial cells can transdifferentiate into mesenchymal cells through a process termed endothelial- mesenchymal transition (EndMT) and that this can give rise to activated myofibroblasts involved in the development of fibrotic diseases. Transforming growth factor β (TGF-β) has a central role in fibrogenesis by modulating the fibroblast phenotype and function, inducing myofibroblast transdifferentiation and promoting matrix accumulation. In addition, TGF-β by inducing EndMT may further contribute to the development of fibrosis. Despite extensive investigation of the pathogenesis of fibrotic diseases, no effective treatment strategies are available. Delineation of the mechanisms responsible for initiation and progression of fibrotic diseases is crucial for the development of therapeutic strategies for the treatment of the disease. In this review, we summarize the role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases and discuss their therapeutic potential.
•Stress early in life can slow recovery from fearful events in adulthood.•Early life stress (ELS) persistently changes prefrontal cortex function in adults.•After ELS, prefrontal neurons were more ...excitatory in response to stimuli.•Prefrontal high-gamma local field potentials (LFPs) were lost after ELS.
Stress experienced early in development can have profound influences on developmental trajectories and ultimately behaviors in adulthood. Potent stressors during brain maturation can profoundly disrupt prefrontal cortical areas in particular, which can set the stage for prefrontal-dependent alterations in fear regulation and risk of drug abuse in adulthood. Despite these observations, few studies have investigated in vivo signaling in prefrontal signals in animals with a history of early life stress (ELS). Here, rats with ELS experienced during the first post-natal week were then tested on a conditioned suppression paradigm during adulthood. During conditioned suppression, electrophysiological recordings were made in the ventral medial prefrontal cortex (vmPFC) during presentations of a fear-associated cue that resolved both single-unit activity and local field potentials (LFPs). Relative to unstressed controls, ELS-experienced rats showed greater fear-related suppression of lever pressing. During presentations of the fear-associated cue (CS+), neurons in the vmPFC of ELS animals showed a significant increase in the probability of excitatory encoding relative to controls, and excitatory phasic responses in the ELS animals were reliably of higher magnitude than Controls. In contrast, vmPFC neurons in ELS subjects better discriminated between the shock-associated CS+ and the neutral (“safe”) CS− cue than Controls. LFPs recorded in the same locations revealed that high gamma band (65–95 Hz) oscillations were strongly potentiated in Controls during presentation of the fear-associated CS+ cue, but this potentiation was abolished in ELS subjects. Notably, no other LFP spectra differed between ELS and Controls for either the CS+ or CS−. Collectively, these data suggest that ELS experience alters the neurobehavioral functions of PFC in adulthood that are critical for processing fear regulation. As such, these alterations may also provide insight into increased susceptibility to other PFC-dependent processes such as risk-based choice, motivation, and regulation of drug use and relapse in ELS populations.
Aqueous film forming foams (AFFFs) have been released at fire training facilities for several decades resulting in the contamination of soil and groundwater by per- and polyfluoroalkyl substances ...(PFASs). AFFF compositions are proprietary and may contain a broad range of PFASs for which the chemical structures and degradation products are not known. In this study, high resolution quadrupole-time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS) in combination with data processing using filtering strategies was applied to characterize and elucidate the PFASs present in concrete extracts collected at a fire training ground after the historical use of various AFFF formulations. Twelve different fluorochemical classes, representing more than 60 chemicals, were detected and identified in the concrete extracts. Novel PFASs homologues, unmonitored before in environmental samples such as chlorinated PFSAs, ketone PFSAs, dichlorinated PFSAs and perfluoroalkane sulphonamides (FASAs) were detected in soil samples collected in the vicinity of the fire training ground. Their detection in the soil cores (from 0 to 2 m) give an insight on the potential mobility of these newly identified PFASs.
•PFASs were investigated at a AFFF impacted fire training ground (FTG).•AFFF impacted concrete and soil core samples (0–2 m) were analysed by LC-QTOF-MS/MS.•Mass defect filtering strategy allowed the detection of untargeted PFASs.•Novel PFASs homologues were detected in soil and concrete samples collected at the FTG.
The “Six Ws” of sustainable development risks Gomez‐Valencia, Manuela; Gonzalez‐Perez, Maria Alejandra; Gomez‐Trujillo, Ana Maria
Business strategy and the environment,
November 2021, 2021-11-00, 20211101, Letnik:
30, Številka:
7
Journal Article
Recenzirano
Risk management in an organization represents a decisive function in seizing opportunities and managing the risks that can affect a business's reputation, prosperity, growth, value creation, ...stakeholder engagement, long‐term survival, and a firm's contribution to sustainable development. For this paper, we conduct a systematic literature review of 148 indexed studies and uses the “Six Ws” (what, who, why, where, when, and how) approach to understand the linkages between sustainability and risk management. This study's findings reveal that the management of environmental, social, and governance (ESG) concerns plays a mitigation's function on business risks.
The Apolipoprotein E-ε4 allele (APOE-ε4) is the strongest genetic risk factor for late onset Alzheimer disease (AD). ApoE plays a critical role in amyloid-β (Aβ) accumulation in AD, and genetic ...deletion of the murine ApoE gene in mouse models results in a decrease or inhibition of Aβ deposition. The association between the presence of ApoE and amyloid in amyloidoses suggests a more general role for ApoE in the fibrillogenesis process. However, whether decreasing levels of ApoE would attenuate amyloid pathology in different amyloidoses has not been directly addressed. Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease characterized by the presence of widespread parenchymal and vascular Danish amyloid (ADan) deposition and neurofibrillary tangles. A transgenic mouse model for FDD (Tg-FDD) is characterized by parenchymal and vascular ADan deposition. To determine the effect of decreasing ApoE levels on ADan accumulation in vivo, we generated a mouse model by crossing Tg-FDD mice with ApoE KO mice (Tg-FDD+/−/ApoE−/−). Lack of ApoE results in inhibition of ADan deposition up to 18 months of age. Additionally, our results from a genetic screen of Tg-FDD+/−/ApoE−/− mice emphasize the significant role for ApoE in neurodegeneration in FDD via glial-mediated mechanisms. Taken together, our findings suggest that the interaction between ApoE and ADan plays a key role in FDD pathogenesis, in addition to the known role for ApoE in amyloid plaque formation in AD.
Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also ...constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.
We show here that human pancreatic islets highly express C3, which is both secreted and present in the cytosol. Within isolated human islets, C3 expression correlates with type 2 diabetes (T2D) donor ...status, HbA1c, and inflammation. Islet C3 expression is also upregulated in several rodent diabetes models. C3 interacts with ATG16L1, which is essential for autophagy. Autophagy relieves cellular stresses faced by β cells during T2D and maintains cellular homeostasis. C3 knockout in clonal β cells impaired autophagy and led to increased apoptosis after exposure of cells to palmitic acid and IAPP. In the absence of C3, autophagosomes do not undergo fusion with lysosomes. Thus, C3 may be upregulated in islets during T2D as a cytoprotective factor against β cell dysfunction caused by impaired autophagy. Therefore, we revealed a previously undescribed intracellular function for C3, connecting the complement system directly to autophagy, with a broad potential importance in other diseases and cell types.
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•Islet C3 expression is upregulated in human T2D and rodent models of diabetes•C3 is present within the cytosol and binds autophagy-related protein 16-1 (ATG16L1)•β cells lacking C3 have impaired autophagy•Intracellular C3 protects β cells from palmitic acid/IAPP-mediated apoptosis
King et al. show that the main complement protein, C3, is expressed intracellularly in pancreatic β cells. C3 binds ATG16L1, thus regulating autophagy and protecting β cells from death from various insults. These findings highlight a novel intracellular protective role of this major immunological protein.
Objectives. The purpose of this work was to study the relationship of metacognition, absorption, and depersonalization in hallucinating patients.
Design. A within‐subjects correlational design was ...employed.
Methods. We formed four groups from a clinical population (schizophrenic patients with hallucinations, schizophrenic patients with no hallucinations but with delusions, schizophrenic patients recovered from positive symptoms, and patients with a non‐psychotic psychiatric disorder) and a non‐clinical control group. All participants were given the Metacognitions Questionnaire (MCQ‐30, Wells & Cartwright‐Hatton, 2004), the Tellegen Absorption Scale (TAS, Tellegen & Atkinson, 1974) and the Cambridge Depersonalization Scale (CDS, Sierra & Berrios, 2000).
Results. Schizophrenic subjects with hallucinations scored significantly higher on the depersonalization scale than any other group, and significantly higher on the absorption scale than any group except for the clinical patient controls. Schizophrenic patients with hallucinations also had significantly more dysfunctional metacognitive beliefs than subjects with no psychiatric pathology. It was further found that the metacognition variable correlated positively with the absorption and depersonalization variables, and that these variables in turn correlated positively with each other. Finally, it should be stressed that the variables that best predict hallucination severity are depersonalization and the MCQ‐30 subscale `Need to control thoughts’.
Conclusions. We discuss the role of metacognitive and dissociative variables in understanding hallucinations and suggest some approaches to their treatment.
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