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PubMed2004

Ets ternary complex transcription factors.

The three ternary complex factors (TCFs) Elk-1, Net and Sap-1 form a subfamily of the E twenty-six (Ets) domain transcription factors. Their characteristic property is the ability to form a ternary nucleoprotein complex with the serum response factor (SRF) over the serum response element (SRE) of the c-fos promoter. The molecular mechanisms that underlie the function and regulation of these factors have been extensively studied and the TCFs are a paradigm for the study of transcriptional regulation in response to extracellular signalling through the mitogen-activated protein (MAP) kinase pathway. As final effectors of multiple signalling pathways and components of protein complexes on immediate early promoters, they represent key elements in the complex and dynamic regulation of gene expression. This review summarises the molecular, structural and biochemical studies that have led to the understanding of the functional domains of the TCFs, ternary complex formation, transcriptional regulation, protein partners and target genes in cell lines. Finally, the emerging studies of the biological roles of the TCFs in vivo will be discussed.

Amino Acid Sequence↗

PubMed2026

Unraveling cadaverine toxicity effect to guide the engineering of robust strain.

End-product inhibition represents a major challenge in the microbial synthesis of various value-added chemicals. Cadaverine, a key monomer for polyamide synthesis, exhibits severe cytotoxicity, limiting its high-titer biosynthesis. Here, transcriptomic analysis and genome-wide library screening were integrated to systematically elucidate the cytotoxic mechanisms of cadaverine in Escherichia coli (E. coli) and identify beneficial genes for enhanced tolerance and overproduction. Transcriptomic analysis revealed that high concentrations of cadaverine disrupted cell membrane integrity and impaired oxidative phosphorylation, leading to redox imbalance and reactive oxygen species (ROS) accumulation. Subsequent genome-wide screening further confirmed these toxicity mechanisms and uncovered crucial cellular defense strategies. Functional validation highlighted the important role of NikR, UbiE, and YcbX in enhancing membrane integrity, restoring respiratory function and ROS homeostasis, or scavenging 6-N-hydroxylaminopurine (6-HAP) to prevent DNA damage. Among these, YcbX emerged as the most effective target for improving production. Consequently, we constructed a robust E. coli strain by implementing a dynamic regulation system for YcbX expression under cadaverine-responsive promoters, which significantly enhanced cadaverine biosynthesis to 87.2 g/L (a 46.8% enhancement). This work provides an in-depth understanding of cadaverine toxicity and tolerance, offering valuable targets and strategies for the rational design of high-performance microbial cell factories for diamines.

6-HAP clearance↗

PubMed2003

Sublethal effects of contamination on the Mediterranean sponge Crambe crambe: metal accumulation and biological responses.

The effect of low levels of pollution on the growth, reproduction output, morphology and survival of adult sponges and settlers of the sponge Crambe crambe were examined. We transplanted sponges from a control area to a contaminated site and measured the main environmental variables (chemical and physical) of both sites during the study period. Except some punctual differences in particulate organic matter, silicates, nitrates, and water motion, most environmental variables in the water were similar at both sites during the study months. Mainly copper, lead and OM concentrations in the sediment, and water motion were significantly higher at the polluted site and may be implicated in the biological effects observed: decrease in the percentage of specimens with embryos, increase in shape irregularity and decrease in growth rate. Individuals naturally occurring at the polluted site and those transplanted there for four months accumulated ten times more copper than either untouched or transplant controls. Although lead concentration in sediment did not differ between sites, native specimens from the contaminated site accumulated this metal more than untouched controls. Vanadium concentration also tended to increase in the sponges living at or transplanted to the contaminated site but this difference was not significant. C. crambe is a reliable indicator of metal contamination since it accumulates copper, lead and vanadium in high amounts. At the contaminated site, sponge growth, fecundity and survival were inhibited, whereas sponge irregularity ending in sponge fission was promoted. All these effects may compromise the structure and dynamics of the sponge populations in sheltered, metal-contaminated habitats.

Animals↗

PubMed2000

Enforced polarisation and locomotion of fibroblasts lacking microtubules.

The polarisation and locomotion of fibroblasts requires an intact microtubule cytoskeleton [1]. This has been attributed to an influence of microtubule-mediated signals on actin cytoskeleton dynamics, either through the generation of active Rac to promote protrusion of lamellipodia [2], or through the modulation of substrate adhesion via microtubule targeting events [3] [4]. We show here that the polarizing role of microtubules can be mimicked by externally imposing an asymmetric gradient of contractility by local application of the contractility inhibitor ML-7. Apolar fibroblasts lacking microtubules could be induced to polarize and to move by application of ML-7 by micropipette to one side of the cell and then to the trailing vertices that developed. The release and retraction of trailing adhesions could be correlated with a relaxation of traction on the substrate and a differential shortening of stress-fibre bundles, with their distal tips relaxed. Although retraction and protrusion in these conditions resembled control cell locomotion, the normal turnover of adhesion sites that form behind the protruding cell front was blocked. These findings show that microtubules are dispensable for fibroblast protrusion, but are required for the turnover of substrate adhesions that normally occurs during cell locomotion. We conclude that regional contractility is modulated by the interfacing of microtubule-linked events with focal adhesions and that microtubules determine cell polarity via this route.

Cell Movement↗

PubMed2004

Targeted inhibition of V(D)J recombination by a histone methyltransferase.

The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.

Animals↗

PubMed2026

Folding a broken genome: the versatile roles of cohesin in genome maintenance.

Cohesin is a protein complex that shapes 3D genome organization through two distinct mechanisms. First, cohesin tethers replicated chromatids from DNA replication until mitosis. This process, known as sister chromatid cohesion, ensures accurate chromosome segregation and enables high-fidelity DNA repair through homologous recombination between the sister chromatids. Second, cohesin organizes the genome during interphase by dynamically extruding chromatin loops, structures that have key roles in gene regulation. Recent work has shown that, in addition to the well-established repair functions of sister chromatid cohesion, cohesin-mediated chromatin looping is closely linked to the repair of DNA double-strand breaks - one of the most toxic DNA lesions. In this Review, we discuss the central roles of cohesin in maintaining genome stability, with emphasis on the cellular response to DNA double-strand breaks. We review how dynamic loop structures facilitate signalling of repair events and promote long-range chromatin motions that underpin the repair process. Overall, its dual mode of action - cohesion and loop extrusion - positions cohesin as a central regulator of chromatin architecture and genome maintenance.

Cohesins↗

PubMed2002

Lung volume dependence of pharyngeal cross-sectional area by acoustic pharyngometry.

Pharyngeal size and the dynamic behavior of the pharynx may be important factors in the modulation of pharyngeal airflow. There are two measures of pharyngeal function: changes in pharyngeal area with lung volume and changes in pharyngeal area in response to externally applied positive pressure. Both measurements have been used for the assessment of pharyngeal function, and both reflect pharyngeal "floppiness." The aim of the present study was to examine the relationship between pharyngeal cross-sectional area, using acoustic reflection technique, and different lung volumes (tidal volume, inspiratory reserve volume, and expiratory reserve volume), to determine whether there are differences in mechanical properties of the pharynx of normal volunteers in response to changes in intrapharyngeal pressure. The acoustic technique was used to assess the pharyngeal cross-sectional area of 40 healthy volunteers (29 men and 11 women) at tidal volume, inspiratory reserve volume, and expiratory reserve volume. In men, the mean pharyngeal area at tidal volume was 3.191 cm2, the mean pharyngeal area at inspiratory reserve volume was 2.976 cm2, and the mean pharyngeal area at expiratory reserve volume was 2.975 cm2. In women, the corresponding pharyngeal area measurements were 2.832, 2.484, and 2.492 cm2. Statistical analysis of results showed that men have a larger pharyngeal cross-sectional area and the pharyngeal airways of men and women act in a similar manner in response to changes in intrapharyngeal pressure, with men having a greater change. Examination of the pharyngeal compliance by acoustic pharyngometry adds to the potential of this technique as a tool for the evaluation of the pharyngeal airway in terms of area and dynamic behavior assessment. This may be of relevance in promotion of the development of upper airway assessment in patients with obstructive sleep apnea.

Acoustics↗

PubMed1999

Op18/stathmin mediates multiple region-specific tubulin and microtubule-regulating activities.

Oncoprotein18/stathmin (Op18) is a regulator of microtubule (MT) dynamics that binds tubulin heterodimers and destabilizes MTs by promoting catastrophes (i.e., transitions from growing to shrinking MTs). Here, we have performed a deletion analysis to mechanistically dissect Op18 with respect to (a) modulation of tubulin GTP hydrolysis and exchange, (b) tubulin binding in vitro, and (c) tubulin association and MT-regulating activities in intact cells. The data reveal distinct types of region-specific Op18 modulation of tubulin GTP metabolism, namely inhibition of nucleotide exchange and stimulation or inhibition of GTP hydrolysis. These regulatory activities are mediated via two-site cooperative binding to tubulin by multiple nonessential physically separated regions of Op18. In vitro analysis revealed that NH(2)- and COOH-terminal truncations of Op18 have opposite effects on the rates of tubulin GTP hydrolysis. Transfection of human leukemia cells with these two types of mutants result in similar decrease of MT content, which in both cases appeared independent of a simple tubulin sequestering mechanism. However, the NH(2)- and COOH-terminal-truncated Op18 mutants regulate MTs by distinct mechanisms as evidenced by morphological analysis of microinjected newt lung cells. Hence, mutant analysis shows that Op18 has the potential to regulate tubulin/MTs by more than one specific mechanism.

Allosteric Site↗

PubMed2001

Estrogen receptors: orchestrators of pleiotropic cellular responses.

Estrogen receptors (ERs) orchestrate both transcriptional and non-genomic functions in response to estrogens, xenoestrogens and signals emanating from growth factor signalling pathways. The pleiotropic and tissue-specific effects of estrogens are likely to be mediated by the differential expression of distinct estrogen receptor subtypes (ERalpha and ERbeta) and their coregulators. The recent analysis of transcription complexes associated with estrogen-responsive promoters has revealed unexpected levels of complexity in the dynamics of ER-mediated transcription. Furthermore, a small fraction of ERs also appears to directly interact with components of the cytosolic signalling machinery. Analysis of the interrelationship between these distinct modes of ER action is likely to reveal novel aspects of estrogen signalling that will impact on nuclear receptor biology and human health.

Animals↗

PubMed2006

L11 domain rearrangement upon binding to RNA and thiostrepton studied by NMR spectroscopy.

Ribosomal proteins are assumed to stabilize specific RNA structures and promote compact folding of the large rRNA. The conformational dynamics of the protein between the bound and unbound state play an important role in the binding process. We have studied those dynamical changes in detail for the highly conserved complex between the ribosomal protein L11 and the GTPase region of 23S rRNA. The RNA domain is compactly folded into a well defined tertiary structure, which is further stabilized by the association with the C-terminal domain of the L11 protein (L11(ctd)). In addition, the N-terminal domain of L11 (L11(ntd)) is implicated in the binding of the natural thiazole antibiotic thiostrepton, which disrupts the elongation factor function. We have studied the conformation of the ribosomal protein and its dynamics by NMR in the unbound state, the RNA bound state and in the ternary complex with the RNA and thiostrepton. Our data reveal a rearrangement of the L11(ntd), placing it closer to the RNA after binding of thiostrepton, which may prevent binding of elongation factors. We propose a model for the ternary L11-RNA-thiostrepton complex that is additionally based on interaction data and conformational information of the L11 protein. The model is consistent with earlier findings and provides an explanation for the role of L11(ntd) in elongation factor binding.

Anti-Bacterial Agents↗

PubMed1999

Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements.

The TGFbeta-related molecule Nodal is required for establishment of the anterior-posterior (A-P) and left-right (L-R) body axes of the vertebrate embryo. In mouse, several discrete sites of nodal activity closely correlate with its highly dynamic expression domains. nodal function in the posterior epiblast promotes primitive streak formation, whereas transient nodal expression in the extraembryonic visceral endoderm is essential for patterning the rostral central nervous system. Asymmetric nodal expression in the developing node and at later stages in left lateral plate mesoderm has been implicated as a key regulator of L-R axis determination. We have analyzed the cis-regulatory elements controlling nodal expression domains during early development. We show that the regulatory sequences conferring node-specific expression are contained in an upstream region of the locus, whereas early expression in the endoderm and epiblast and asymmetric expression at later stages on the left side of the body axis are controlled by a 600-bp intronic enhancer. Targeted deletion of a 100-bp subregion of this intronic enhancer eliminates nodal expression in the early epiblast and visceral endoderm and disrupts asymmetric expression in the node and lateral plate mesoderm. Thus, developmentally regulated nodal expression at distinct tissue sites during A-P and L-R axis formation is potentially controlled by common transcriptional activators.

Animals↗

PubMed1984

Lung compliance changes on high-frequency ventilation in normal dogs.

To test the hypothesis that high-frequency ventilation (HFV) promotes lung stability we compared the temporal course of dynamic lung compliance changes after two inflations on HFV with those occurring on conventional mechanical ventilation (CMV) at two different lung volumes, specifically with and without 5 cmH2O positive end-expiratory pressure (PEEP). In our first set of experiments we ventilated six anesthetized paralyzed dogs first with CMV, then with HFV, then again with CMV using tidal volumes of 15 ml/kg at rates of 16-18 times/min for CMV and less than 90 ml and a rate of 15 Hz for HFV. In our second set of experiments we ventilated six dogs for 4 h, the 1st h with CMV at 0 cmH2O end-expiratory pressure, the 2nd h with CMV with 5 cmH2O PEEP, the 3rd h with HFV at the same mean pleural pressure, and the 4th h again with CMV with 5 cmH2O PEEP. We found the decreases in dynamic compliance with time following hyperinflations were similar on HFV and CMV (P greater than 0.5) at both lung volumes. With the lower lung volume the initial dynamic compliance following hyperinflation also tended to fall progressively from one hour to the next despite the inflations. However, with PEEP the initial dynamic compliance over successive hours tended to rise from one hour to the next. We found that changes in dynamic compliance were not necessarily reflected in the venous admixture or alveolar to arterial O2 partial pressure gradients. We thus conclude that lung stability in normal dogs is not improved during HFV, and blood gases cannot be used to predict compliance changes.

Animals↗

PubMed2006

Group cohesion and social support in exercise classes: results from a danish intervention study.

This study examines the formation of group cohesion and social support in exercise classes among former sedentary adults, participating in a Danish community-based intervention. Furthermore, the aim is to analyze the impact of this process on exercise activity among the participants. A multimethod approach was used, analyzing both survey data and 18 personal interviews collected among 87 participants who completed the intervention project. Analysis was performed according to the grounded theory method. The formation of group cohesion was conditioned by the social composition of the group, the teaching ability by the instructors, and the activity by itself. The cohesive group was characterized by an attitude of mutual support toward exercise activities. This mutual support facilitated development of self-efficacy beliefs among the participants improving their mastery expectation regarding exercise. Manipulating group dynamics may be a promising intervention tool in the promotion of leisure-time physical activity.

Adult↗

PubMed1994

Measuring community competence in the Mississippi Delta: the interface between program evaluation and empowerment.

If political dynamics are included in the definition of community, health promotion programs have a greater potential to recognize that assisting people to empower their communities is as important as assisting them to improve their health. This paper reports on the evaluation methods employed for a health promotion program in a rural poor county of the Mississippi Delta that chose to define community in this way. The evaluation took an action research approach so that the methods would not contradict or interfere with the program's empowerment agenda. The methods required a close and collaborative working relationship among evaluators and local service providers, community leaders, and program staff who defined and operationalized eight dimensions of community competence, determined the units of analysis, and developed the data collection protocol. Emphasis was placed on using the data to engage the program and three communities in a dialogue on how to confront a system with the difficult issues they faced. The findings revealed that after 1 year of implementation, community competence moved from social interactions internal to communities to those more externally focused on mediating with outside institutions and officials. At the same time, measures of self-other awareness and conflict containment showed a decrease or virtual nonexistence.

Adolescent↗

PubMed2025

The impacts of chronic infections on shaping cellular senescence.

Cellular senescence is a fundamental biological process characterized by stable cell cycle arrest, genomic instability, and the acquisition of a proinflammatory secretory phenotype. While senescence is traditionally associated with aging, growing evidence reveals that chronic infections such as viral, bacterial, and protozoan parasites can serve as powerful inducers of senescence, contributing to premature aging and long-term tissue damage. This review explores the diverse mechanisms by which persistent pathogens trigger or sustain senescence in host cells. We highlight how these chronic infections manipulate host DNA repair, mitochondrial dynamics, telomere maintenance, oxidative stress, and immune function to promote senescence and immunosenescence. Emerging findings also reveal how pathogens hijack the host cellular machinery to induce senescence across various tissue types. In many cases, senescence not only enables pathogen persistence but also drives pathological outcomes such as fibrosis, neurodegeneration, cardiomyopathy, and immune exhaustion. Collectively, this emerging evidence highlights a unifying strategy among diverse pathogens: the exploitation of cellular senescence to support chronic infection and promote disease. Understanding how infectious agents drive senescence offers new insights into age-related pathologies and highlights potential therapeutic targets, such as senolytic and senomorphic agents, to mitigate the long-term impacts of chronic infections.

Bacterial infection↗

PubMed1999

Oncogene-mediated downregulation of RECK, a novel transformation suppressor gene.

The RECK gene was initially isolated as a transformation suppressor gene encoding a novel membrane-anchored glycoprotein and later found to suppress tumor invasion and metastasis by regulating matrix metalloproteinase-9. Its expression is ubiquitous in normal tissues, but undetectable in many tumor cell lines and in fibroblastic lines transformed by various oncogenes. The RECK gene promoter has been cloned and characterized. One of the elements responsible for the oncogene-mediated downregulation of mouse RECK gene is the Sp1 site, where the Sp1 and Sp3 factors bind. Sp1 transcription factor family is involved in the basal level of promoter activity of many genes, as well as in dynamic regulation of gene expression; in a majority of cases as a positive regulator, or, as exemplified by the oncogene-mediated suppression of RECK gene expression, as a negative transcription regulator. The molecular mechanisms of the down-regulation of mouse RECK gene and other tumor suppressor genes are just beginning to be uncovered. Understanding the regulation of these genes may help to develop strategies to restore their expression in tumor cells and, hence, suppress the cells' malignant behavior.

Animals↗

PubMedDate not supplied

Development of ToxA and ToxB promoter-driven fluorescent protein expression vectors for use in filamentous ascomycetes.

The green fluorescent protein (GFP) has been established as the premier in vivo reporter for investigations of gene expression, protein localization, and cell and organism dynamics. The fungal transformation vector pCT74, with sGFP under the control of the ToxA promoter from Pyrenophora tritici-repentis, effectively expresses GFP in a diverse group of filamentous ascomycetes. Due to the versatility of ToxA promoter-driven expression of GFP, we constructed an additional set of fluorescent protein expression vectors to expand the color palette of fluorescent markers for use in filamentous fungi. EYFP, ECFP and mRFP1 were successfully expressed from the ToxA promoter in its fungus of origin, P. tritici-repentis, and a distant relative, Verticillium dahliae. Additionally the ToxB promoter from P. tritici-repentis drove expression of sGFP in V. dahliae, suggesting a similar potential to the ToxA promoter for heterologous expression in ascomycetes. The suite of fungal transformation vectors presented here promise to be useful for a variety of fungal research applications.

Ascomycota↗

PubMed1989

[Blood rheologic disorders in patients with polycythemia vera and their correction by therapeutic erythrocytapheresis].

The rheologic blood properties were studied in patients with polycythemia vera (PV) before and after erythrocytapheresis. The patients with PV showed a complex of hemorheologic disorders (high blood viscosity at different rates of deviation, intensified red blood cell aggregation, decreased deformability of these cells) found to be implicated in the disease pathogenesis. Erythrocytapheresis promoted the improvement of the rheologic characteristics such as dynamic blood viscosity and the red blood cell aggregation ratio.

Blood Coagulation Disorders↗