Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and ...transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gα
-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase DOPA decarboxylase (DDC), the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.
The Arabidopsis PIF4 and BES1/BZR1 transcription factors antagonize light signaling by facilitating co‐activated expression of a large number of cell wall‐loosening and auxin‐related genes. While ...PIF4 directly activates expression of these targets, BES1 and BZR1 activity switch from a repressive to an activator function, depending on interaction with TOPLESS and other families of regulators including PIFs. However, the complexity of this regulation and its role in diurnal control of plant growth and brassinosteroid (BR) levels is little understood. We show by using a protein array that BES1, PIF4, and the BES1‐PIF4 complex recognize different DNA elements, thus revealing a distinctive cis‐regulatory code beneath BES1‐repressive and PIF4 co‐activation function. BES1 homodimers bind to conserved BRRE‐ and G‐box elements in the BR biosynthetic promoters and inhibit their expression during the day, while elevated PIF4 competes for BES1 homodimer formation, resulting in de‐repressed BR biosynthesis at dawn and in response to warmth. Our findings demonstrate a central role of PIF4 in BR synthesis activation, increased BR levels being essential to thermomorphogenic hypocotyl growth.
Synopsis
Plant elongation in response to warmth and light is tightly controlled by steroid hormone‐sensitive gene expression, but the dynamic regulation of this circuitry remains unresolved. Here, crosstalk between the Arabidopsis transcription factors PIF4 and BES1 is shown to activate brassinosteroid (BR) synthesis and adjust seed stem growth to the daily changes of environmental stimuli.
Interaction with PIF4 switches BES1 activity from a repressive to an activator function.
BES1 binds as a homodimer to conserved BRRE and G‐box elements in the promoters of BR biosynthetic and BES‐DOWN genes.
The PIF4‐BES1 complex recognizes a CATGTG motif or PBE‐element that is enriched in the promoters of PIF‐UP and PIF + BES‐UP targets.
Accumulation of PIF4 at warm temperatures up‐regulates BR levels by competing for BES1 homodimerization.
The transcription factor PIF4 confers adaptation of plant hormone activation during warmth‐dependent hypocotyl growth.
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are transcription cofactors implicated in the contractile and profibrotic activation of fibroblasts. ...Fibroblast contractile function is important in alveologenesis and in lung wound healing and fibrosis. As paralogs, YAP and TAZ may have independent or redundant roles in regulating transcriptional programs and contractile function. Using IMR-90 lung fibroblasts, microarray analysis, and traction microscopy, we tested whether independent YAP or TAZ knockdown alone was sufficient to limit transcriptional activation and contraction in vitro. Our results demonstrate limited effects of knockdown of either YAP or TAZ alone, with more robust transcriptional and functional effects observed with combined knockdown, consistent with cooperation or redundancy of YAP and TAZ in transforming growth factor β1 (TGFβ1)-induced fibroblast activation and contractile force generation. The transcriptional responses to combined YAP/TAZ knockdown were focused on a relatively small subset of genes with prominent overrepresentation of genes implicated in contraction and migration. To explore potential disease relevance of our findings, we tested primary human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis and confirmed that YAP and TAZ combined knockdown reduced the expression of three cytoskeletal genes,
,
, and
. We then compared the contribution of these genes, along with YAP and TAZ, to contractile function. Combined knockdown targeting YAP/TAZ was more effective than targeting any of the individual cytoskeletal genes in reducing contractile function. Together, our results demonstrate that YAP and TAZ combine to regulate a multigene program that is essential to fibroblast contractile function.
The COVID-19 lockdown in Spain caused abrupt changes for students following the Bachelor's Degree in Civil Engineering at the University of Burgos when face-to-face classes switched to online ...teaching. The recovery of face-to-face teaching after lockdown meant that classes were taught with obligatory social distancing and the use of masks. Teachers were therefore unable to interact with students closely, to perceive their facial expressions during class, or to conduct group work. The changes to civil-engineering teaching linked to the COVID-19 pandemic and the lessons that civil-engineering teachers learnt from the new teaching scenarios are studied in this paper. The reflections of teachers throughout all three stages of the pandemic (pre-pandemic and lockdown, during lockdown, and post-lockdown), and the qualitative and mixed analysis of their responses to a survey of open-ended questions contributed to the identification of six major lessons: (1) asking questions and using real-time quiz tools enliven classes and help to determine which concepts to emphasize for proper student understanding; (2) autonomous student learning can be promoted through the provision of supplementary documentation and the digitalization of solutions to classroom exercises; (3) virtual site visits and real visual examples interspersed with explanations bring concepts closer to their real applications; (4) the delivery of projects in the form of audio-recorded presentations enable their distribution, so that other students can also learn from them as well as the students who created them; (5) online videoconferences, adapted to the concepts that are addressed, facilitate fast and flexible communication with students; and (6) online continuous-assessment exams can promote better student learning patterns and final-exam preparation. Nevertheless, these six lessons were drawn from the experience of teachers at a small Spanish university where the period of solely online teaching during the COVID-19 pandemic lasted only four months. Thus, it would be interesting to analyze the experience of civil-engineering teachers at larger universities and universities that had longer periods of solely online teaching. A study of the level of implementation of the six aspects when the pandemic is declared over might also be worthwhile.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A variety of G protein-coupled receptors (GPCRs) have been implicated in the pathogenesis of pulmonary fibrosis, largely through their promotion of profibrotic fibroblast activation. By contrast, ...recent work has highlighted the beneficial effects of Gαs-coupled GPCRs on reducing fibroblast activation and fibrosis. This review highlights how fibrosis-promoting and -inhibiting GPCR signaling converges on downstream signaling and transcriptional effectors, and how the diversity and dynamics of GPCR expression challenge efforts to identify effective therapies for idiopathic pulmonary fibrosis (IPF). Next-generation strategies to overcome these challenges, focusing on target selection, polypharmacology, and personalized medicine approaches, are discussed as a path towards more effective GPCR-targeted therapies for pulmonary fibrosis.
Multiple GPCR ligand/receptor pairs are implicated in IPF, and clinical trials are currently underway targeting GPCR pathways for the treatment of IPF.Individual GPCRs can promote profibrotic or antifibrotic phenotypes in lung fibroblasts, depending on the receptor class and downstream signaling pathways.The convergence of downstream pathways on common signaling and transcriptional mechanisms integrates diverse GPCR effects and may provide a path to overcome redundancy.Signaling programs downstream of GPCR signaling are also essential for alveolar epithelial regeneration and repair, highlighting the need to identify strategies that account for this complexity.
The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on ...maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients.
Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk RR 2.01 confidence interval (CI) 1.66-2.44), placental abruption (RR 2.14 CI 1.23-3.70), premature rupture of membranes (RR 1.43 CI 1.04-1.95), and neonatal death (RR 2.58 CI 1.41-4.73). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score.
SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.
The effect of preventive human papillomavirus (HPV) vaccination on the reduction of the cervical cancer (CC) burden will not be known for 30 years. Therefore, it's still necessary to improve the ...procedures for CC screening and treatment. The objective of this study was to identify and characterize cellular targets that could be considered potential markers for screening or therapeutic targets. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CCs and 12 healthy cervical epitheliums using microarrays. A total of 997 genes were deregulated, and 21 genes that showed the greatest deregulation were validated using qRT-PCR. The 6 most upregulated genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored in 29 low-grade cervical intraepithelial neoplasias (CIN1) and 21 high-grade CIN (CIN2/3) to investigate whether they could differentiate CC and CIN2/3 (CIN2+) from CIN1 and controls. CCNB2, PRC1, and SYCP2 were mostly associated with CC and CDC20, NUSAP1, and CDKN3 were also associated with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1 to detect CIN2+ was approximately 90%. The proteins encoded by all 6 genes were shown upregulated in CC by immunohistochemistry. The association of these markers with survival was investigated in 42 CC patients followed up for at least 42 months. Only CDKN3 was associated with poor survival and it was independent from clinical stage (HR = 5.9, 95%CI = 1.4-23.8, p = 0.01). CDKN3 and NUSAP1 may be potential targets for the development of screening methods. Nevertheless, further studies with larger samples are needed to define the optimal sensitivity and specificity. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be not only a screening and survival marker but a potential therapeutic target in CC. However, whether it's indispensable for tumor growth remains to be demonstrated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colombia, a country that is very vulnerable to climate change, has played a positive role in international climate negotiations. Paradoxically, Colombia is also the sixth largest coal exporter ...globally, and its government has adopted policies to further increase the country's production of coal and other fossil fuels. This article explores to what extent the national government reproduces a powerful paradigm - namely, that fossil fuel extraction is necessary for development - and how this resonates at the sub-national level. We find that the government's narrative has evolved to accommodate Colombia's changing national circumstances and public criticism. Though counternarratives exist, they have struggled to propose credible nationwide alternatives to extractive-based development, thus reinforcing the belief that extraction-based development is unavoidable. We describe how government narratives constitute an obstacle to both supply-side policies to restrict fossil fuel development and to transitional assistance policies to adjust to shifts in the global coal market.
Key policy insights
The view that fossil fuel extraction is necessary for development is a powerful barrier to supply - side climate policy.
This view also hinders the formulation of transitional assistance policy.
Empirical evidence that fossil fuel extraction seldom leads to equitable development is not enough to overcome this view.
Narratives on fossil fuel-based development continuously adjust to prevailing economic development paradigms and contemporary development challenges.
The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, involved in mitosis, is upregulated in cervical cancer (CC). We investigated CDKN3 mRNA as a survival biomarker and potential therapeutic target ...for CC. CDKN3 mRNA was measured in 134 CC and 25 controls by quantitative PCR. A 5-year survival study was conducted in 121 of these CC patients. Furthermore, CDKN3-specific siRNAs were used to investigate whether CDKN3 is involved in proliferation, migration, and invasion in CC-derived cell lines (SiHa, CaSki, HeLa). CDKN3 mRNA was on average 6.4-fold higher in tumors than in controls (p = 8 x 10-6, Mann-Whitney). A total of 68.2% of CC patients over expressing CDKN3 gene (fold change ≥ 17) died within two years of diagnosis, independent of the clinical stage and HPV type (Hazard Ratio = 5.0, 95% CI: 2.5-10, p = 3.3 x 10-6, Cox proportional-hazards regression). In contrast, only 19.2% of the patients with lower CDKN3 expression died in the same period. In vitro inactivation of CDKN3 decreased cell proliferation on average 67%, although it had no effect on cell migration and invasion. CDKN3 mRNA may be a good survival biomarker and potential therapeutic target in CC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The complex RuCp(H2O‐κO)(mPTA)2(CF3SO3)3·MeOH (4·MeOH) was synthesized and characterized by spectroscopic techniques and its crystal structure determined by single‐crystal X‐ray diffraction (mPTA = ...N‐methyl‐1,3,5‐triaza‐7‐phosphaadamantane). The catalytic activity of 4 for the redox isomerization of 2‐cyclohexen‐1‐ol into cyclohexanone was studied in water, methanol/water, and biphasic systems, reaching the highest conversion rate in biphasic water/cyclohexane (1:1) at pH 1.7 and under N2. The aqueous phase containing 4 was recycled up to 7 consecutive runs, reaching a total turnover number (TON) of 471 without significant losses of catalyst. Therefore, this reaction is a unique procedure for the isomerization of cyclic allylic alcohols without metal contamination of the product. The catalytic reaction mechanism was studied by nuclear magnetic resonance (NMR), showing that the reaction probably proceeds through the formation of an intermediate in which the substrate is η2‐coordinated to the metal.
The paper discusses the catalytic activity of RuCp(H2O‐κO)(mPTA)2(CF3SO3)3 for the isomerization of the cyclic allylic alcohol 2‐cyclohexen‐1‐ol with good conversion and negligible metal losses.
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