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At least 991 records · Page 55Linked to original sources
PubMed1991

Analysis of the binding proteins and activity of the long terminal repeat of Moloney murine leukemia virus during differentiation of mouse embryonal carcinoma cells.

Mouse embryonal carcinoma (EC) cell lines were established which carry the stably integrated chloramphenicol acetyltransferase (CAT) gene under the control of the transcriptional elements of the long terminal repeat (LTR) of Moloney murine leukemia virus. The activity of three elements of the stably integrated LTR was analyzed in undifferentiated EC cells (stable CAT assay). Results of the study are summarized as follows. (i) In the stable assay, the promoter region of the LTR was inactive in undifferentiated ECA2 and F9 cells, and the level of the activity was 10(-4) of that in NIH 3T3 cells. (ii) In contrast to the results of the transient assay, the enhancer was active in undifferentiated ECA2 cells and in F9 cells. It activated CAT activity more than 60-fold and about 8-fold in ECA2 cells and F9 cells, respectively. (iii) Suppression by ELP, the embryonal LTR-binding protein, was more pronounced in the stable assay than in the transient assay. These data suggest that, when compared with NIH 3T3 cells, a major factor for the inactivity of the LTR in EC cells is the inefficiency of the promoter in this assay. Transcriptional activity of the LTR was analyzed during the differentiation of EC cells. In the case of ECA2 cells, the magnitude of activation by the enhancer did not change during differentiation. The activity of the promoter increased about 10-fold, and the suppression by ELP became negligible 4 days after the induction of differentiation. Upon differentiation of F9 cells, the activity of the enhancer increased more than 300-fold, but the promoter remained inactive. The pattern of LTR-binding proteins also varied during the differentiation of EC cells. Our present data suggest that the activity of LTR elements as assayed by the stable assay differs from the activity as assayed by the transient assay. It also indicates that the activity of these elements exhibits cell-type-specific changes during the differentiation of EC cells.

Animals↗
PubMed1999

Neural crest can form cartilages normally derived from mesoderm during development of the avian head skeleton.

The lateral wall of the avian braincase, which is indicative of the primitive amniote condition, is formed from mesoderm. In contrast, mammals have replaced this portion of their head skeleton with a nonhomologous bone of neural crest origin. Features that characterize the local developmental environment may have enabled a neural crest-derived skeletal element to be integrated into a mesodermal region of the braincase during the course of evolution. The lateral wall of the braincase lies along a boundary in the head that separates neural crest from mesoderm, and also, neural crest cells migrate through this region on their way to the first visceral arch. Differences in the availability of one skeletogenic population versus the other may determine the final composition of the lateral wall of the braincase. Using the quail-chick chimeric system, this investigation tests if populations of neural crest, when augmented and expanded within populations of mesoderm, will give rise to the lateral wall of the braincase. Results demonstrate that neural crest can produce cartilages that are morphologically indistinguishable from elements normally generated by mesoderm. These findings (1) indicate that neural crest can respond to the same cues that both promote skeletogenesis and enable proper patterning in mesoderm, (2) challenge hypotheses on the nature of the boundary between neural crest and mesoderm in the head, and (3) suggest that changes in the allocation of migrating cells could have enabled a neural crest-derived skeletal element to replace a mesodermal portion of the braincase during evolution.

Animals↗
PubMed1986

The termini of extrachromosomal linear copia elements.

Extrachromosomal linear copia elements were isolated and cloned from cultured Drosophila melanogaster cells. Four full length copia recombinants were characterised. Each contains a full sized copy of copia bounded by its direct repeats. The sequences of the ends of the copia inserts were determined. All of the termini are identical to those of genomic copias except for a single base deletion from one end of one clone. These results suggest that the priming for initiation of copia reverse transcription differs from normal retroviral models. Southern blot analysis of uncloned full length copia circles shows that approximately 50% correspond to the predicted circularisation product of such linears. We propose that this class of circles and the linear DNAs described here are precursors to integrated genomic copia elements.

Animals↗
PubMed2026

The Convergence of Antimicrobial Resistance and Virulence in Streptococcus pneumoniae: A Molecular and Clinical Perspective.

Antimicrobial resistance (AMR) and virulence have traditionally been viewed as competing traits in bacterial evolution due to fitness costs. However, Streptococcus pneumoniae has emerged as a paradigm of successful coevolution, with multidrug-resistant clones simultaneously maintaining or enhancing pathogenic potential. This review examines the molecular mechanisms, epidemiological patterns, and clinical consequences of the convergence between AMR and virulence in Streptococcus pneumoniae. Resistance to β-lactams is driven by mosaic penicillin-binding protein genes (pbp1a, pbp2b, pbp2x), while macrolide resistance is mediated primarily by the erm(B) gene (MLS phenotype) and mef(A/E)-msr(D) genes encoding an efflux system. These determinants are frequently co-localized on integrative and conjugative elements, ICEs, (e.g., Tn916 family) within successful clonal complexes such as CC271/320 and lineages including ST320 and GPSC10. Contrary to the classical fitness cost hypothesis, compensatory epistasis, capsular recombination, metabolic adaptations, and intra-serotype phenotypic variation enable certain clones to combine high-level resistance to β-lactams, macrolides, and tetracyclines with enhanced colonization, biofilm formation, immune evasion, and invasive capacity. Post-pneumococcal conjugate vaccine (PCV) surveillance reveals the persistence and expansion of these high-risk lineages, contributing to treatment-refractory invasive pneumococcal disease (IPD), increased morbidity, and mortality. Although PCVs have reduced vaccine-type resistant strains in some settings, serotype replacement and emerging metabolic genotypes continue to drive adaptation. This review highlights the need for integrated genomic surveillance, novel therapeutics (e.g., omadacycline, lefamulin, endolysins), monoclonal antibodies, and next-generation vaccines targeting both resistance and conserved virulence determinants. A multifaceted strategy combining antimicrobial stewardship, strengthened surveillance, and innovative interventions is essential to curb the evolving threat of resistant and virulent S. pneumoniae.

Streptococcus pneumoniae↗
PubMed1993

3-D computation of E fields by the volume-surface integral equation (VSIE) method in comparison with the finite-integration theory (FIT) method.

An algorithm has been developed for calculation of 3-dimensional E fields by the volume-surface integral equation (VSIE) method. Integration over surface elements is performed by elementary analytical formulas, assuming a linear interpolation of surface charges. Grid points at electrical interfaces are split off, well considering the E field behavior at these contours, specifically at sharp bends and multimedia junctions. Averaging procedures are utilized in order to avoid undefined or infinite values at critical points. The VSIE is solved by iteration using GMRES ("general minimum residuum") solver on a SUN workstation SPARC-IPX or Cray XMP, whereby convergence speed decreases considerably as the heterogeneity of the problem increases. Computation time (e.g., 20 min on a supercomputer for approximately 30,000 cells) needs to be reduced by further code development. Results for 3-D test cases (plane wave illuminating a layered cylinder) generally agree well with the finite-integration-theory (FIT) method if high E field gradients occur perpendicular to electrical boundaries. The VSIE method predicts slightly higher E fields only in critical regions. On the other hand, the FIT method at present is more efficient with respect to computation time for large domains with high cell numbers (> 100,000 cells).

Algorithms↗
PubMed2005

The pathology of breast cancer and the role of the histopathology laboratory.

Histopathology plays an important part in determining the treatment strategy for women with breast cancer, with the evaluation of breast specimens determining the surgical and the oncological therapeutic options used. The correct approach to specimens requires integration of clinical and imaging findings. This work is not trivial. It is time-consuming and skilled, and requires (and has in place) safeguards and checks in the form of national audit and quality-control schemes. The pathobiology of breast cancer is diverse, and the current taxonomy, rooted in morphological interpretation, has been underscored by molecular observations, such as the relationship of E-cadherin mutations to lobular carcinomas. Investigation of ductal carcinoma of no special type (NST) reveals covert tumour types, such as those with basal or myoepithelial features, whose distinctive features are only now being widely recognised. With the rise of modern molecular techniques, the demise of diagnostic histopathology has been predicted, but, for now and the intermediate future, the histopathologist remains a key element of the integrated breast-care team.

Breast Neoplasms↗
PubMed1996

Induction of longevity by cytoplasmic transfer of a linear plasmid in Podospora anserina.

In Podospora anserina the longevity inducing linear plasmid pAL2-1 was transferred from the extrachromosomal long-lived mutant AL2 to the short-lived wild-type strain A. The resulting strain, AL2-IV, exhibited the long-lived phenotype. In the short-lived progeny of crosses between this strain and wild-type strain A, the plasmid was absent. In contrast, all long-lived progeny contained both the autonomous plasmid as well as copies of it integrated in the mitochondrial DNA (mtDNA). Molecular analysis revealed that the integrated plasmid copies most likely resulted from a de novo integration of the autonomous element and the generation of AT-linker sequences at the integration site. We conclude that once the plasmid is present in mitochondria of a particular genetic background, it is able to integrate into the mtDNA and to induce longevity.

Ascomycota↗
PubMed1993

Use of mathematical models for understanding the dynamics of gene amplification.

Recently it has been suggested that high levels of cancer drug resistance and poor prognosis are strongly associated with gene or oncogene amplification (GA). It has been further suggested that the molecular mechanisms underlying GA may be different for different genes, and that different amplification mechanisms may function concurrently or sequentially in the same gene. The aim of this review is to demonstrate the use of mathematical models in studying these intricate dynamics. We have provided mathematical models for the generation of extrachromosomal elements, their autonomous replication and equal or unequal mitotic segregation, the integration of the extrachromosomal elements within the chromosomes, and chromosomal GA in one or many unlinked genes. Using this formal description one can examine the potential role of each GA mechanism in the generation of specific distributions of gene-copy number in a cell population, under various levels of selection stringency. Thus one can specify the conditions for the emergence of drug-resistant mutants prior to selection, as well as the relationships between the stringency of the selecting environment and the characteristics of the resultant cellular phenotype.

Animals↗
PubMed1994

The computation of contour information in complex objects.

Perceptual organisation, and especially the computation of contour information, has been the object of considerable interest in the last few years. In the first part of the paper we review recent accounts on the mechanisms involved in the processing of contour. In the second part we report an experiment designed to examine (1) how physical parameters such as spatial proximity and collinearity of elements affect the integration of global contour in objects and (2) whether the activation of stored representations of objects facilitates the computation of contour. Incomplete forms varying in the spacing and the alignment of line segments on their contour were used as stimuli in a matching task. Subjects were asked to decide which of two laterally displayed figures matched a reference form presented previously. The matching target and the distractor were physically identical but differed in their orientation. In one condition the reference object was always an outline drawing of an object. In a second condition the reference object was either a complete object or a more or less identifiable incomplete form. Little variation in performance was found for forms having continuous and discontinuous contour up to a spacing of 5 pixels (10.8 min) between elements. Response times and errors increased abruptly beyond this limit. This effect occurred in the two conditions of reference stimulus, suggesting that the computation of contour information is more affected by physical constraints at early processes than by high-level processes involving activation of stored structural representations of objects.

Cognition↗
PubMedDate not supplied

Use of the ecosystem approach to population health: the case of mercury contamination in aquatic environments and riparian populations, Andean Amazon, Napo River Valley, Ecuador.

BACKGROUND: Driven by accelerating transformation of land use in the Amazon, studies addressing the impacts of deforestation and mercury (Hg) leaching on the geophysical, biological, social, health, economic and political systems of Amazonian countries are crucial to evaluate the population health risks of these rapid changes. METHODS: We used an ecosystem approach, integrating Hg measurements with socio-cultural and politico-economic elements, to provide an integral analysis and comprehensive solutions. RESULTS: Our interdisciplinary research in the Ecuadorian Andean Amazon has shown that comestible fish and riparian communities which rely on fish as a major protein source have mercury levels that could potentially cause subtle but deleterious population health alterations. A parallel study identified deforestation and soil erosion as a significant source of mercury to the aquatic ecosystem. INTERPRETATION: The analysis of these results in conjunction with the prevailing socio-cultural and politico-economic context allowed us to identify economic trends, and especially petroleum exploitation, as pivotal in the deforestation/mercury-exposure dynamic. In collaboration with public health authorities, we shared our results with local health stakeholders, including public health care staff, federal government agencies, researchers and local communities, in such a way as to promote sustainable land use practices and the nutritional benefits of fish eating while reducing toxic exposures.

Animals↗
PubMed2001

A new regulatory region of the IL-2 locus that confers position-independent transgene expression.

Although the promoter/enhancer of the IL-2 gene mediates inducible reporter gene expression in vitro, it cannot drive consistent expression in transgenic mice. The location and existence of any regulatory elements that could open the IL-2 locus in vivo have remained unknown, preventing analysis of IL-2 regulation in developmental contexts. In this study, we report the identification of such a regulatory region, marked by novel DNase-hypersensitive sites upstream of the murine IL-2 promoter in unstimulated and stimulated T cells. Inclusion of most of these sites in an 8.4-kb IL-2 promoter green fluorescent protein transgene gives locus control region-like activity. Expression is efficient, tissue specific, and position independent. This transgene is expressed not only in peripheral T cells, but also in immature thymocytes and thymocytes undergoing positive selection, in agreement with endogenous IL-2 expression. In contrast, a 2-kb promoter green fluorescent protein transgene, lacking the new hypersensitive sites, is expressed in only a few founder lines, and expression is dysregulated in CD8(+) cells. Thus, the 6.4 kb of additional upstream IL-2 sequence contains regulatory elements that provide integration site independence and differential regulation of transgene expression in CD8 vs CD4 cells.

3' Untranslated Regions↗
PubMed2003

ETHYLENE RESPONSE FACTOR1 integrates signals from ethylene and jasmonate pathways in plant defense.

Cross-talk between ethylene and jasmonate signaling pathways determines the activation of a set of defense responses against pathogens and herbivores. However, the molecular mechanisms that underlie this cross-talk are poorly understood. Here, we show that ethylene and jasmonate pathways converge in the transcriptional activation of ETHYLENE RESPONSE FACTOR1 (ERF1), which encodes a transcription factor that regulates the expression of pathogen response genes that prevent disease progression. The expression of ERF1 can be activated rapidly by ethylene or jasmonate and can be activated synergistically by both hormones. In addition, both signaling pathways are required simultaneously to activate ERF1, because mutations that block any of them prevent ERF1 induction by any of these hormones either alone or in combination. Furthermore, 35S:ERF1 expression can rescue the defense response defects of coi1 (coronative insensitive1) and ein2 (ethylene insensitive2); therefore, it is a likely downstream component of both ethylene and jasmonate signaling pathways. Transcriptome analysis in Col;35S:ERF1 transgenic plants and ethylene/jasmonate-treated wild-type plants further supports the notion that ERF1 regulates in vivo the expression of a large number of genes responsive to both ethylene and jasmonate. These results suggest that ERF1 acts downstream of the intersection between ethylene and jasmonate pathways and suggest that this transcription factor is a key element in the integration of both signals for the regulation of defense response genes.

Arabidopsis↗
PubMed2006

Dielectrophoresis microsystem with integrated flow cytometers for on-line monitoring of sorting efficiency.

Dielectrophoresis (DEP) and flow cytometry are powerful technologies and widely applied in microfluidic systems for handling and measuring cells and particles. Here, we present a novel microchip with a DEP selective filter integrated with two microchip flow cytometers (FCs) for on-line monitoring of cell sorting processes. On the microchip, the DEP filter is integrated in a microfluidic channel network to sort yeast cells by positive DEP. The two FCs detection windows are set upstream and downstream of the DEP filter. When a cell passes through the detection windows, the light scattered by the cell is measured by integrated polymer optical elements (waveguide, lens, and fiber coupler). By comparing the cell counting rates measured by the two FCs, the collection efficiency of the DEP filter can be determined. The chips were used for quantitative determination of the effect of flow rate, applied voltage, conductivity of the sample, and frequency of the electric field on the sorting efficiency. A theoretical model for the capture efficiency was developed and a reasonable agreement with the experimental results observed. Viable and non-viable yeast cells showed different frequency dependencies and were sorted with high efficiency. At 2 MHz, more than 90% of the viable and less than 10% of the non-viable cells were captured on the DEP filter. The presented approach provides quantitative real-time data for sorting a large number of cells and will allow optimization of the conditions for, e.g., collecting cancer cells on a DEP filter while normal cells pass through the system. Furthermore, the microstructure is simple to fabricate and can easily be integrated with other microstructures for lab-on-a-chip applications.

Cell Separation↗
PubMed1991

Identification and DNA sequence of a new Bacteroides fragilis insertion sequence-like element.

A new Bacteroides fragilis insertion sequence (IS)-like element has been identified, cloned, and sequenced. The element is 1598 base pairs in length. It is flanked by a 15-base pair imperfect inverted repeat and contains a large open reading frame which could encode a 430 amino acid protein. There is an 8-base pair duplication of genomic DNA sequences at the site of integration. One copy of the IS-like element is integrated within the 5' upstream sequence of the metallo-beta-lactamase gene ccrA, cloned from B. fragilis TAL3636. The IS-like element is integrated 19 bp upstream of the predicted initiation codon and, therefore, probably provides the transcriptional start signals for the CcrA gene.

Amino Acid Sequence↗
PubMed1998

Integration of the quorum-sensing system in the regulatory networks controlling virulence factor synthesis in Erwinia chrysanthemi.

The expI-expR locus drives a quorum-sensing system in the phytopathogenic bacterium, Erwinia chrysanthemi. Purified ExpR, an N-acyl homoserine lactone-responsive regulatory protein, binds to the promoter/operator region of the expI and expR genes. DNase I footprinting experiments showed that ExpR protects the regions between -66 and -40 from the P1 transcription initiation site of expl and between -54 and -18 from the expR transcription initiation site P1. The protected region overlaps the two expR promoters, P1 and P2, suggesting that ExpR exerts a negative control on its own gene expression. This assertion is reinforced by the fact that the addition of OHHL dissociates the ExpR-expR DNA complex. In contrast, the location of the ExpR binding site on the expI gene suggests an activator function, as reported for the pel genes. Moreover, ExpR is able to induce DNA bending. In vivo and in vitro studies revealed that CRP functions as an activator of expR expression, but as a repressor of expI transcription. A second level of control of expR and expI occurs through the PecS repressor, a regulator of pectinase synthesis. PecS represses expI expression, while ExpR activates pecS transcription, suggesting the existence of a mutual control between pecS and the expI-expR system in E. chrysanthemi. Regulation of pectinase synthesis in soft rot Erwinia appears to be a complex network of multiple cross-acting regulatory elements. A model that integrates these regulatory elements is proposed.

4-Butyrolactone↗
PubMed2003

The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells.

Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV-8]) is a gamma-2-herpesvirus responsible for Kaposi's sarcoma as well as primary effusion lymphoma (PEL). KSHV is a lymphotropic virus that has pirated many mammalian genes involved in inflammation, cell cycle control, and angiogenesis. Among these is the early lytic viral G protein-coupled receptor (vGPCR), a homologue of the human interleukin-8 (IL-8) receptor. When expressed, vGPCR is constitutively active and can signal via mitogen- and stress-activated kinases. In certain models it activates the transcriptional potential of NF-kappaB and activator protein 1 (AP-1) and induces vascular endothelial growth factor (VEGF) production. Despite its importance to the pathogenesis of all KSHV-mediated disease, little is known about vGPCR activity in hematopoietic cells. To study the signaling potential and downstream effects of vGPCR in such cells, we have developed PEL cell lines that express vGPCR under the control of an inducible promoter. The sequences required for tetracycline-mediated induction were cloned into a plasmid containing adeno-associated virus type 2 elements to enhance integration efficiency. This novel plasmid permitted studies of vGPCR activity in naturally infected KSHV-positive lymphocytes. We show that vGPCR activates ERK-2 and p38 in PEL cells. In addition, it increases the transcription of reporter genes under the control of AP-1, NF-kappaB, CREB, and NFAT, a Ca(2+)-dependent transcription factor important to KSHV lytic gene expression. vGPCR also increases the transcription of KSHV open reading frames 50 and 57, thereby displaying broad potential to affect viral transcription patterns. Finally, vGPCR signaling results in increased PEL cell elaboration of KSHV vIL-6 and VEGF, two growth factors involved in KSHV-mediated disease pathogenesis.

Cyclic AMP Response Element-Binding Protein↗
PubMed1990

Interactive effects of O3, cytochalasin D, and vinblastine on transepithelial transport and cytoskeleton in rat airways.

Cytoskeletal perturbations and associated changes in transepithelial transport in rat airways were analyzed after in vivo treatment with cytochalasin D or vinblastine or exposure to ozone (O3). Exposure of O3 or cytochalasin D, but not vinblastine, increased permeability in the bronchoalveolar region. Combined treatment with cytochalasin D and O3 did not increase the effect seen with each agent alone. However, treatment with vinblastine plus 0.8 ppm O3 resulted in a slight enhancement of permeability over that seen with O3 alone. This enhancement was not seen with 2 ppm O3. When cytochalasin and vinblastine treatment were combined, a synergistic effect on bronchoalveolar permeability was seen, suggesting participation of both microfilamentous and microtubular cytoskeletal elements in maintaining the integrity of the bronchoalveolar epithelium. Potentially harmful effects of O3 on cytoskeletal elements were confirmed in rat lung epithelial cells in culture. O3 exposure produced reversible changes in microfilamentous structures comparable to those produced by cytochalasin D. The results of these studies support the hypotheses that the cytoskeleton has a central role in maintenance of respiratory epithelial integrity and that a target for O3 toxicity may be the components of cytoskeleton. These results, however, do not rule out the possibility that treatment with cytoskeleton destabilizing drugs leads to the release of mediators, which in turn contribute to the airway epithelial dysfunction and increased permeability.

Animals↗
PubMed2005

Activation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons.

In mammals, degeneration of peripheral auditory neurons constitutes one of the main causes of sensorineural hearing loss. Unfortunately, to date, pharmacological interventions aimed at counteracting this condition have not presented complete effectiveness in protecting the integrity of cochlear neural elements. In this context, the protein kinase C (PKC) family of enzymes are important signalling molecules that play a role in preventing neurodegeneration after nervous system injury. The present study demonstrates, for the first time, that the PKC signalling pathway is directly neurotrophic to axotomised spiral ganglion neurons (SGNs). We found that PKCbetaI was strictly expressed by postnatal and adult SGNs both in situ and in vitro. In cultures of SGNs, we observed that activators of PKC, such as phorbol esters and bryostatin 1, induced neuronal survival and neurite regrowth in a manner dependent on the activation of PKCbetaI. The neuroprotective effects of PKC activators were suppressed by pre-treatment with LY294002 (a PI3K inhibitor) and with U0126 (a MEK inhibitor), indicating that PKC activators promote the survival and neurite outgrowth of SGNs by both PI3K/Akt and MEK/ERK-dependent mechanisms. In addition, whereas combining the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was shown to provide only an additive effect on SGN survival, the interaction between PKC and neurotrophin signalling gave rise to a synergistic increase in SGN survival. Taken together, the data indicate that PKCbetaI activation represents a key factor for the protection of the integrity of neural elements in the cochlea.

Animals↗