Organismal development and function requires multiple and accurate signal transduction pathways to ensure that proper balance between cell proliferation, differentiation, inactivation, and death is ...achieved. Cell death via apoptotic caspase signal transduction is extensively characterized and integral to this balance. Importantly, the view of apoptotic signal transduction has expanded over the previous decades. Subapoptotic caspase signaling has surfaced as mechanism that can promote the adoption of a range of cellular fates. An emerging mechanism of subapoptotic caspase signaling is the activation of the caspase‐activated DNase (CAD) through controlled cleavage of the inhibitor of CAD (ICAD). CAD‐induced DNA breaks incite a DNA damage response, frequently invoking p53 signaling, that transduces a change in cell fate. Cell differentiation and senescence are fates demonstrated to arise from CAD‐induced DNA breaks. Furthermore, an apparent consequence of CAD activity is also emerging, as a potential source of oncogenic mutations. This review will discuss the mechanisms underlying CAD‐induced DNA breaks and highlight how CAD activity promotes diverse cell fates.
The caspase‐activated DNase (CAD) is a driver of apoptotic DNA fragmentation, but developing observations have implicated the activity of the nuclease in the adoption of nonapoptotic cellular fates. Nonapoptotic cell fate outcomes arising from CAD‐induced DNA breaks included differentiation, senescence, and transformation. This review will discuss the mechanisms underlying CAD‐induced DNA breaks and highlight how CAD activity promotes diverse cell fates.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Accumulation of extracellular matrix (ECM) components and increased matrix-metalloprotease (MMPs) activity are hallmarks of fibrosis. We developed an ELISA for quantification of MMP-9 derived ...collagen type III (CO3) degradation.
A monoclonal antibody targeting a specific MMP-9 cleaved fragment of CO3 was used for development of a competitive ELISA. The assay was investigated in serum and tissues from bile duct ligated rats (BDL).
The ELISA showed no cross-reaction with either intact CO3, or other collagens. The intra- and inter-assay CV were below 10%. Liver fibrosis was demonstrated in BDL animals by semi quantitative scoring (
P
<
0.0001). Serum levels of CO3-610 increased 2.5 fold in BDL animals (
P
<
0.001). The CO3-610 levels were 5 fold higher in ex vivo cultures of fibrotic livers compared to controls (
P
<
0.001).
We have developed a novel ELISA for measuring a specific fragment CO3 generated by MMP-9 important in pathogenesis of liver fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mesenchymal (stromal) stem cells (MSCs) constitute populations of mesodermal multipotent cells involved in tissue regeneration and homeostasis in many different organs. Here we performed ...comprehensive characterization of the transcriptional and epigenomic changes associated with osteoblast and adipocyte differentiation of human MSCs. We demonstrate that adipogenesis is driven by considerable remodeling of the chromatin landscape and de novo activation of enhancers, whereas osteogenesis involves activation of preestablished enhancers. Using machine learning algorithms for in silico modeling of transcriptional regulation, we identify a large and diverse transcriptional network of pro-osteogenic and antiadipogenic transcription factors. Intriguingly, binding motifs for these factors overlap with SNPs related to bone and fat formation in humans, and knockdown of single members of this network is sufficient to modulate differentiation in both directions, thus indicating that lineage determination is a delicate balance between the activities of many different transcription factors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
A growing number of studies suggest that maternal stress during pregnancy promotes atopic disorders in the offspring. This is the first systematic review to address prenatal maternal ...stress (PNMS) and the subsequent risk of atopy‐related outcomes in the child.
Methods
The review was performed in accordance to the PRISMA criteria. We searched and selected studies in PubMed, Scopus, Embase and PsychINFO until November 2014.
Results
Sixteen (with 25 analyses) of 426 identified articles met the review criteria. Five main PNMS exposures (negative life events, anxiety/depression, bereavement, distress and job strain) and five main atopic outcomes (asthma, wheeze, atopic dermatitis, allergic rhinitis and IgE) were assessed across the studies. Overall, 21 of the 25 analyses suggested a positive association between PNMS and atopic outcomes. Of the 11 exposure–response analyses reported, six found statistically significant trends.
Conclusion
This systematic review suggests a relationship between maternal stress during pregnancy and atopic disorders in the child. However, the existing studies are of diverse quality. The wide definitions of often self‐reported stress exposures imply a substantial risk for information bias and false‐positive results. Research comparing objective and subjective measures of PNMS exposure as well as objective measures for atopic outcome is needed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The serum response factor (SRF) binds to coactivators, such as myocardin-related transcription factor-A (MRTF-A), and mediates gene transcription elicited by diverse signaling pathways. ...SRF/MRTF-A-dependent gene transcription is activated when nuclear MRTF-A levels increase, enabling the formation of transcriptionally active SRF/MRTF-A complexes. The level of nuclear MRTF-A is regulated by nuclear G-actin, which binds to MRTF-A and promotes its nuclear export. However, pathways that regulate nuclear actin levels are poorly understood. Here, we show that MICAL-2, an atypical actin-regulatory protein, mediates SRF/MRTF-A-dependent gene transcription elicited by nerve growth factor and serum. MICAL-2 induces redox-dependent depolymerization of nuclear actin, which decreases nuclear G-actin and increases MRTF-A in the nucleus. Furthermore, we show that MICAL-2 is a target of CCG-1423, a small molecule inhibitor of SRF/MRTF-A-dependent transcription that exhibits efficacy in various preclinical disease models. These data identify redox modification of nuclear actin as a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.
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•MICAL-2 activates SRF/MRTF-A-dependent gene transcription•MICAL-2 induces a redox modification of nuclear actin•MICAL-2 induces the nuclear localization of MRTF-A•The SRF/MRTF-A pathway inhibitor CCG-1423 inhibits MICAL-2
MICAL-2, an atypical actin-regulatory protein, induces redox-dependent depolymerization of nuclear actin, which decreases levels of nuclear G-actin and promotes retention of MRTF-A in the nucleus. Thus, redox modification of nuclear actin is a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Non-alcoholic steatohepatitis (NASH) signified by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis is a growing cause of chronic liver disease, cirrhosis, and hepatocellular ...carcinoma. Hepatic fibrosis resulting from accumulation of extracellular matrix proteins secreted by hepatic myofibroblasts plays an important role in disease progression. Activated hepatic stellate cells (HSCs) have been identified as the primary source of myofibroblasts in animal models of hepatotoxic liver injury; however, so far HSC activation and plasticity have not been thoroughly investigated in the context of NASH-related fibrogenesis. Here we have determined the time-resolved changes in the HSC transcriptome during development of Western diet- and fructose-induced NASH in mice, a NASH model recapitulating human disease. Intriguingly, HSC transcriptional dynamics are highly similar across disease models pointing to HSC activation as a point of convergence in the development of fibrotic liver disease. Bioinformatic interrogation of the promoter sequences of activated genes combined with loss-of-function experiments indicates that the transcriptional regulators ETS1 and RUNX1 act as drivers of NASH-associated HSC plasticity. Taken together, our results implicate HSC activation and transcriptional plasticity as key aspects of NASH pathophysiology.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during ...irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.
Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in ...osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
What does it mean to read the gospels “before the book”? For centuries, the way people have talked about the gospels has been shaped by ideas that have more to do with the printing press and modern ...notions of the author than they do with ancient writing and reading practices. Gospels Before the Book challenges several subtle yet problematic assumptions about authors, books, and publication at work in early Christian studies. The author explores a host of underappreciated elements of ancient textual culture, such as unfinished texts, accidental publication, postpublication revision, and multiple authorized versions of the same work. Turning to the gospels, he argues the earliest readers and users of the text we now call the Gospel according to Mark treated it not as a book published by an author but as an unfinished, open, and fluid collection of notes (hypomnēmata). The Gospel according to Matthew, then, would not be regarded as a separate book published by a different author but, rather, as a continuation of the same unfinished gospel tradition. Similarly, it is not the case that, of the five different endings in the textual tradition, one is “right” and the others are “wrong.” Rather, each ending represents its own effort to fill in what some perceived to be lacking in the Gospel according to Mark. The text of the Gospel according to Mark is better understood when approached as unfinished notes than as a book published by an author. Larsen also offers a new methodological framework for future scholarship on early Christian gospels.
Heteroarenes are important structural moieties in many chemical industry fields. A highly efficient Pd/Cu-catalyzed C−H arylation method for a range of heterocycles has been discovered. It was found ...that the key to the success of this transformation is a combination of a palladium catalyst and a well-defined copper cocatalyst. The efficiency and low loadings of catalyst (0.25 mol %) and cocatalyst (1 mol %) together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.
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IJS, KILJ, NUK, PNG, UL, UM
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