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PubMed2006

Importance of receptor usage, Fli1 activation, and mouse strain for the stem cell specificity of 10A1 murine leukemia virus leukemogenicity.

Murine leukemia viruses (MuLV) induce leukemia through a multistage process, a critical step being the activation of oncogenes through provirus integration. Transcription elements within the long terminal repeats (LTR) are prime determinants of cell lineage specificity; however, the influence of other factors, including the Env protein that modulates cell tropism through receptor recognition, has not been rigorously addressed. The ability of 10A1-MuLV to use both PiT1 and PiT2 receptors has been implicated in its induction of blast cell leukemia. Here we show that restricting receptor usage of 10A1-MuLV to PiT2 results in loss of blast cell transformation capacity. However, the pathogenicity was unaltered when the env gene is exchanged with Moloney MuLV, which uses the Cat1 receptor. Significantly, the leukemic blasts express erythroid markers and consistently contain proviral integrations in the Fli1 locus, a target of Friend MuLV (F-MuLV) during erythroleukemia induction. Furthermore, an NB-tropic variant of 10A1 was unable to induce blast cell leukemia in C57BL/6 mice, which are also resistant to F-MuLV transformation. We propose that 10A1- and F-MuLV actually induce identical (erythro)blastic leukemia by a mechanism involving Fli1 activation and cooperation with inherent genetic mutations in susceptible mouse strains. Furthermore, we demonstrate that deletion of the Icsbp tumor suppressor gene in C57BL/6 mice is sufficient to confer susceptibility to 10A1-MuLV leukemia induction but with altered specificity. In summary, we validate the significance of the env gene in leukemia specificity and underline the importance of a complex interplay of cooperating oncogenes and/or tumor suppressors in determining the pathogenicity of MuLV variants.

Animals↗
PubMed2006

Raver1 is an integral component of muscle contractile elements.

Raver1, a ubiquitously expressed protein, was originally identified as a ligand for metavinculin, the muscle-specific isoform of the microfilament-associated protein vinculin. The protein resides primarily in the nucleus, where it colocalises and may interact with polypyrimidine-tract-binding protein, which is involved in alternative splicing processes. During skeletal muscle differentiation, raver1 translocates to the cytoplasm and eventually targets the Z-line of sarcomeres. Here, it colocalises with metavinculin, vinculin and alpha-actinin, all of which have biochemically been identified as raver1 ligands. To obtain more information about the potential role of raver1 in muscle structure and function, we have investigated its distribution and fine localisation in mouse striated and smooth muscle, by using three monoclonal antibodies that recognise epitopes in different regions of the raver1 protein. Our immunofluorescence and immunoelectron-microscopic results indicate that the cytoplasmic accumulation of raver1 is not confined to skeletal muscle but also occurs in heart and smooth muscle. Unlike vinculin and metavinculin, cytoplasmic raver1 is not restricted to costameres but additionally represents an integral part of the sarcomere. In isolated myofibrils and in ultrathin sections of skeletal muscle, raver1 has been found concentrated at the I-Z-I band. A minor fraction of raver1 is present in the nuclei of all three types of muscle. These data indicate that, during muscle differentiation, raver1 might link gene expression with structural functions of the contractile machinery of muscle.

Actins↗
PubMed1999

Efficient integration of short interspersed element-flanked foreign DNA via homologous recombination.

We investigated whether mouse short interspersed elements (SINEs) could influence the recombination frequency of foreign DNA. Vectors harboring a reporter gene in combinations of SINEs B1 and/or B2 or a portion of long interspersed element-1 were prepared and tested in vitro by a colony assay using HC11 murine mammary epithelial cells and in vivo by microinjection into fertilized mouse eggs. In transfected HC11 cells, the number of colonies surviving G418 selection increased by 3.5-fold compared with control when the reporter was flanked by fused B1-B2 sequences. Similar results were obtained from microinjection study; in fetuses 11.5 days post coitum, transgene positives in control and SINE-flanked vectors were 16 and 53%, respectively. Individual B1- and B2-harboring vectors showed equivalent activities with each other, as determined by the colony assay (2.8-fold versus 3.2-fold compared with control). We determined the contribution of homologous recombination to the SINE-mediated increase in integration frequency through a polymerase chain reaction-based strategy; in more than half of embryos transgenes underwent homologous recombinations involving B1 sequences. These results demonstrate that the SINE sequences can increase the integration rate of foreign DNA and that such an increase is most likely due to the enhancement of homologous recombination.

Animals↗
PubMed2003

De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease.

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and eventual renal failure. Various types of mutations in the renal chloride channel gene, CLCN5, have been identified in patients with this disease. We studied a Spanish patient with Dent's disease and found, by polymerase chain reaction amplification of the CLCN5 exons, an abnormally large exon 11. Sequencing analysis revealed that this was attributable to the insertion in codon 650 of an Alu element of the "young" Ya5 subfamily. The Alu element was inserted with the same orientation as the CLCN5 gene and arose de novo on the maternal chromosome. Polymorphism analysis indicated that the insertion occurred in the germline of the maternal grandfather. The presence of a long poly(A) tract and evidence for a 16-bp target-site duplication implied that the Alu element was integrated by retrotransposition. This mutation predicts a truncated ClC-5 protein that lacks part of the carboxy-terminus and is likely to result in loss of function of the chloride channel. Insertions of Alu sequences, which are rarely found in coding regions, have occasionally been reported to cause other genetic diseases. However, this is the first report of a retrotransposon insertion in the CLCN5 gene associated with Dent's disease.

Alu Elements↗
PubMed1991

Isolation of virus-like (VL30) elements from the Q10 and D regions of the major histocompatibility complex.

Previous studies from our laboratory have described two endogenous provirus-like sequences in a series of cosmids spanning the TL region of the major histocompatibility complex (MHC) of normal C57BL/10 mice. At least one of these viruses shares similarities with VL30 elements. To determine if additional VL30-like retroviral elements are integrated in the MHC, we constructed a cosmid library using DNA from a radiation leukemia virus (RadLV)-transformed cell line derived from C57BL/6 mice. The library was first screened using the H-2III (5') probe, which detects Class I genes of the H-2 complex. In the primary screening 163 H-2III positives were isolated. The H-2III-positive isolates were then hybridized with an AKR-derived virus probe, EcoB/S, which contains sequences from both the pol and the env genes of the virus. Nine virus-positive isolates were detected. Localization of these cosmid isolates containing viral sequences within the H-2 complex was done utilizing low-copy probes and confirmed using previously mapped cosmid isolates from other laboratories. We report here the isolation and characterization of VL30-like elements from the Qa and D regions of the MHC of several inbred mouse strains.

AKR murine leukemia virus↗
PubMed1982

Viral mechanisms of carcinogenesis.

Several kinds of virus can cause cancer. The various viruses with oncogenic potential probably act through different mechanisms and depend on different host factors. The tumour viruses with small genomes are best understood and may be regarded as transposable genetic elements. By integrating into host cell chromosomal DNA, they may cause mutations and chromosomal rearrangements that predispose to cancer. The insertion of viral promoter sequences adjacent to certain host genes can lead to ectopic gene expression resulting in neoplasia. There is growing evidence, however, that the most strongly oncogenic strains of small DNA and RNA viruses carry 'oncogenes' that encode 'transforming' proteins. Papovavirus early proteins interact with cellular proteins involved in the control of cell proliferation. Many, but not all, of the transforming proteins of retroviruses are located at the plasma membrane and exhibit protein kinase activity, phosphorylating tyrosine residues. Most of the oncogenes of retroviruses studied so far are derived from cellular genes which may play important roles in regulating normal cell proliferation and differentiation. Retrovirus oncogenes may therefore be regarded as kidnapped host factors placed under the control of infectiously transmitted promoter elements. A variety of other host factors and exogenous cofactors affect the course of viral carcinogenesis, from influencing initial infection to immunological responses to chronic infection. Lastly, the endogenous viral genomes, which are inherited as host genetic elements, should themselves be considered as host factors that interact with exogenous carcinogens such as chemicals and ionizing radiation.

Animals↗
PubMed2000

Integrated palliative care within a general hospital.

The goal of the project was to integrate essential elements of palliative care into the regular duties of an internal ward located in a general hospital serving a rural area. To achieve this goal, the medical and nursing staff was moderately expanded, which was made possible by a grant from the Deutsche Krebshilfe, and training and supervision were instituted. Patients with malignant diseases in advanced and terminal phases were enrolled in the project and evaluated using a specifically designed documentation system. On average, 8.5 (18%) of the 46 beds on the ward were occupied by patients being cared for as part of the project at any one time. Effective relief of pain, nausea and respiratory distress were documented. For those dying in the hospital, a single room and the presence of family members were possible in the majority of cases. A high impact on the team became apparent through an anonymous questionnaire given during supervision. The project shows that it is possible to integrate palliative care into the work of a regular internal medical ward, with positive consequences for the patients and the team.

Delivery of Health Care, Integrated↗
PubMed1994

Altered expression of a novel cellular gene as a consequence of integration of human T cell lymphotropic virus type 1.

By analysing a genomic DNA clone derived from the human T cell lymphotropic virus type 1 (HTLV-1)-infected cell line, TL-Su, we found that an integrated HTLV-1 provirus interrupted the poly(A) signal-containing exon of a novel gene, RY-1. Nucleotide sequence analysis of a cDNA derived from Jurkat cells revealed that the normal RY-1 mRNA could encode a novel protein that has an unique primary structure, suggesting that a nucleic acid binding property was involved. Proviral integration led to an accumulation of aberrant RY-1 mRNA species in the cells. All the aberrant RY-1 cDNAs derived from TL-Su cells terminated at the poly(A) site of the R region of the HTLV-1 long terminal repeat and initiated in the intron, approx. 800 bp upstream from the putative second exon. Furthermore, another intron, downstream from this position, remained unspliced in some of the cDNAs. In addition to the activation by the integrated viral elements of cryptic promoters located upstream, mechanisms involving altered rates of degradation or transport from the nucleus to the cytoplasm of intron-containing RNA were suggested.

Amino Acid Sequence↗
PubMed2005

[Long-term stability of body experience after in-patient group psychotherapy with concentrative movement therapy].

Body experience of 34 patients was investigated two years after the end of treatment with Concentrative Movement Therapy (KBT) in an in-patient integrative psychotherapy. Change in body experience at the end of treatment and after the two year period was compared to symptomatic strain and the amount of interpersonal problems. Body experience was rather restricted in the beginning of treatment. The improvement of body experience during treatment showed to be stable after two years, as did the symptomatic strain. Interpersonal problems were not reduced as much during treatment but in the follow-up period. Patients with benefit from KBT treatment through a better approach to their body, felt more bodily self-confident at the end of treatment. They also had less feelings of insecurity and apprehension concerning their body than those who could profit little from KBT. In both groups a reduction of symptomatic strain was found. Patients with little profit from KBT had higher symptomatic and interpersonal strain and more feelings of insecurity concerning their body in the beginning of the treatment. Their improvement at the time of follow-up was low. Results are discussed regarding the relevance of different elements of integrative in-patient therapy and the possibility of differential indications for body-oriented psychotherapy.

Exercise Movement Techniques↗
PubMed1980

The structure of unstable constitutive revertants of mutant galOP-308::IS2-I.

The isolation and characterization of three unstable and constitutive revertants of mutant galOP-308 of E. coli is described. In this mutant an IS2 element is integrated between the promoter and the first structural gene of the galactose operon, and exerts a strong polar effect on the expression of the three galactose genes. In the three revertants under investigation it was observed that relief of polarity and constitutive expression of the gal-operon were accompanied by the deletion of 90% of the IS2 sequence and of various lengths of the adjacent sequences including the gal-promoter. We conclude from this result that the transcription termination signals causing strong polarity were located on the deleted part of IS2, and that in our revertants the galactose genes are now under the control of a new promoter which is apparently unstable.

Chromosome Deletion↗
PubMed2005

Ab initio identification of putative human transcription factor binding sites by comparative genomics.

BACKGROUND: Understanding transcriptional regulation of gene expression is one of the greatest challenges of modern molecular biology. A central role in this mechanism is played by transcription factors, which typically bind to specific, short DNA sequence motifs usually located in the upstream region of the regulated genes. We discuss here a simple and powerful approach for the ab initio identification of these cis-regulatory motifs. The method we present integrates several elements: human-mouse comparison, statistical analysis of genomic sequences and the concept of coregulation. We apply it to a complete scan of the human genome. RESULTS: By using the catalogue of conserved upstream sequences collected in the CORG database we construct sets of genes sharing the same overrepresented motif (short DNA sequence) in their upstream regions both in human and in mouse. We perform this construction for all possible motifs from 5 to 8 nucleotides in length and then filter the resulting sets looking for two types of evidence of coregulation: first, we analyze the Gene Ontology annotation of the genes in the set, searching for statistically significant common annotations; second, we analyze the expression profiles of the genes in the set as measured by microarray experiments, searching for evidence of coexpression. The sets which pass one or both filters are conjectured to contain a significant fraction of coregulated genes, and the upstream motifs characterizing the sets are thus good candidates to be the binding sites of the TF's involved in such regulation. In this way we find various known motifs and also some new candidate binding sites. CONCLUSION: We have discussed a new integrated algorithm for the "ab initio" identification of transcription factor binding sites in the human genome. The method is based on three ingredients: comparative genomics, overrepresentation, different types of coregulation. The method is applied to a full-scan of the human genome, giving satisfactory results.

Algorithms↗
PubMed2005

Humanising medical education through faculty development: linking self-awareness and teaching skills.

BACKGROUND: We conducted a longitudinal faculty development programme for medical school faculty, focused on enhancing learner-centred teaching skills, by integrating traditional elements of education, focusing on knowledge, skills and attitudes, with the non-traditional process elements of community building, self-awareness and relationship formation. METHODS: This year-long programme enrolled faculty from a range of clinical departments at a single institution. The participants gathered for day-long sessions in each of 9 months and also met at lunchtime once a month for "booster" meetings. Sessions were organised according to content areas identified as relevant to enhancing teaching skills. In addition to each content area, a variety of experiential and process learning methods were incorporated and modelled in each session. The impact of the programme was assessed using self-report data after each session, and together with paired interviews at the completion of the programme. EVALUATION: Programme attendance was 97%. Qualitative thematic and content analysis showed that faculty reported renewed energy and enthusiasm for teaching, as well as skills mastery. Faculty also reported significant improvements in self-awareness and habits of lifelong learning. Many faculty members felt that a singular benefit of the programme was developing and nurturing personal as opposed to instrumental relationships. CONCLUSIONS: It is feasible to successfully convene clinical faculty from different departments in the same faculty development programme with little or no concern for competition and conflict. The key to success is integrating content and process dimensions into a framework of community building and collective engagement. From the participants' perspective, skills and confidence, which by self-report increased for all participants, was less consequential than the opportunity to learn about themselves and their relationships to others in a safe environment. We have conducted this programme for 5 successive years.

Curriculum↗
PubMed2001

The role of nitrogen-efficient cultivars in sustainable agriculture.

To improve nitrogen (N) efficiency in agriculture, integrated N management strategies that take into consideration improved fertilizer, soil, and crop management practices are necessary. This paper reports results of field experiments in which maize (Zea mays L.) and oilseed rape (Brassica napus L.) cultivars were compared with respect to their agronomic N efficiency (yield at a given N supply), N uptake efficiency (N accumulation at a given N supply), and N utilization efficiency (dry matter yield per unit N taken up by the plant). Under conditions of high N supply, significant differences among maize cultivars were found in shoot N uptake, soil nitrate depletion during the growing season, and the related losses of nitrate through leaching after the growing season. Experiments under conditions of reduced N supply indicated a considerable genotypic variation in reproductive yield formation of both maize and oilseed rape. High agronomic efficiency was achieved by a combination of high uptake and utilization efficiency (maize), or exclusively by high uptake efficiency (rape). N-efficient cultivars of both crops were characterized by maintenance of a relatively high N-uptake activity during the reproductive growth phase. In rape this trait was linked with leaf area and photosynthetic activity of leaves. We conclude that growing of N-efficient cultivars may serve as an important element of integrated nutrient management strategies in both low- and high-input agriculture.

Agriculture↗
PubMed2005

Cyclic changes in the affinity of protein-DNA interactions drive the progression and regulate the outcome of the Tn10 transposition reaction.

The Tn10 transpososome is a DNA processing machine in which two transposon ends, a transposase dimer and the host protein integration host factor (IHF), are united in an asymmetrical complex. The transitions that occur during one transposition cycle are not limited to chemical cleavage events at the transposon ends, but also involve a reorganization of the protein and DNA components. Here, we demonstrate multiple pathways for Tn10 transposition. We show that one series of events is favored over all others and involves cyclic changes in the affinity of IHF for its binding site. During transpososome assembly, IHF is bound with high affinity. However, the affinity for IHF drops dramatically after cleavage of the first transposon end, leading to IHF ejection and unfolding of the complex. The ejection of IHF promotes cleavage of the second end, which is followed by restoration of the high affinity state which in turn regulates target interactions.

DNA↗
PubMedDate not supplied

[Load shift-total hip replacement--numerical and clinical evaluation of a new concept of adaptive stem fixation].

AIM: The new load-shift fixation concept pursues the goal of an adaptive change of geometrical characteristics of the in-situ hip replacement. In this study a preclinical and clinical evaluation was performed. METHODS: By three-dimensional, dynamic finite element calculation the biomechanical properties of the prosthesis were analyzed in the early postoperative and long-term configuration. By clinical (20 +/- 10 months) and radiological (18 +/- 10 months) follow-up of a first series of implants (n = 20) the primary functional status of the prosthesis was examined in vivo. RESULTS: The preclinical results revealed that the metaphyseal micromotions are reduced significantly with the diaphyseal fit of the stem postoperatively. By absorption of a biodegradable element (spreader) integrated into the tip of the stem a change of stem geometry associated with loss of the diaphyseal fit occurs. This results in a complete shifting of load transmission into the metaphyseal area. In the clinical situation the postoperative Harris hip score averaged 92.9 +/- 10.5 points. Only in two patients did reversible episodes of thigh pain occur. The radiological analysis of bone remodeling phenomena pointed to a physiological load transmission. There was no evidence of loosening or osteolysis. On radiology, stem tapering could be demonstrated. CONCLUSION: On the basis of these promising preclinical and early clinical results the innovative load-shift prosthesis should now be further evaluated in prospective long-term studies.

Aged↗
PubMed2000

Integration of women's health into an internal medicine core curriculum for medical students.

The authors describe their year-long collaboration to analyze and integrate the elements of women's health into their medical school's core curriculum in internal medicine for the third-year clerkship. Such a process was necessary because the current curriculum was inadequate in its treatment of women's health (e.g., little or no coverage of issues pertaining to women in teaching about certain disorders; lack of female subjects in many research studies; study designs' using standards derived from manifestations of diseases in men; the cross-discipline aspects of women's health). The authors illustrate the new curriculum by discussing the revised module in pulmonary medicine; they detail the steps they took to uncover problems and omissions in the existing curriculum and in the literature on the topic, and how they remedied these. (For example, in a case involving a man with pulmonary embolus, one of the new questions for students is "What questions would you ask if this patient were a woman?") They comment on the challenges they faced in revising the curriculum, including lack of protected time, lack of sufficient data about women's health, inherent sex and gender bias in the literature and educational materials, need to make students aware of the importance of sex and gender considerations in patient care, and the ingrained bias of faculty, including the authors. Their process can be adapted and used to integrate curricula in other emerging interdisciplinary fields, such as cross-cultural medicine and gay and lesbian health. The authors conclude that collaboration between students and faculty, as illustrated in their own efforts, is one way to ensure that future practitioners are optimally trained to treat patients in the ever-changing field of medicine.

Attitude of Health Personnel↗
PubMed1996

Quantitative clinical measure of spasticity in children with cerebral palsy.

OBJECTIVE: This investigation developed an objective measure to quantify the degree of spasticity. DESIGN: Specifications included a single variable that integrated key elements characterizing spasticity: velocity, range of motion, and resistance to passive motion. A dynamometer at a children's hospital quantified the passive resistance of the hamstrings to knee extension for a range of motion at 4 different speeds for the prospective descriptive investigation. PATIENTS: A convenience sample of six children with able bodies and 17 children with spastic diplegic cerebral palsy volunteered. DATA PROCESSING: Torque-angle data were processed to calculate the work done by the machine on the children for each speed and then determine the slope of the work-velocity curves. This slope was considered to be the measure of spasticity and it was hypothesized that children with cerebral palsy would have a greater slope than children with able bodies. An independent test determined whether a significant difference existed between groups (p < .05). RESULTS: Torque-angle data for children with able bodies indicated little change in passive resistance as a function of speed. Similar data for children with cerebral palsy indicated larger resistive torques with increasing speed. Slope from the work-velocity data was close to zero for children with able bodies [.003 J/(degrees/sec)], while the corresponding slope for children with cerebral palsy was approximately 10 times greater [.031 J/(degrees/sec)] and significantly different (p < .05). CONCLUSION: The slope of the work-velocity data integrates three major components characterizing spasticity, it is a single number that can easily be evaluated and interpreted in a clinical setting, and it utilizes a machine that is available at many centers.

Adolescent↗
PubMed1993

Role of disulfide bonds in maintaining the structural integrity of the sheath of Leptothrix discophora SP-6.

Isolated sheaths of Leptothrix discophora SP-6 (ATCC 51168) were tested for susceptibility to degradation by a variety of chemical denaturants and lytic enzymes and found to be resistant to many reagents and enzyme treatments. However, disulfide bond-reducing agents such as dithiothreitol (DTT), beta-mercaptoethanol, sodium cyanide, and sodium sulfite degraded the sheath, especially at elevated pH (pH 9) and temperature (50 degrees C). DTT and beta-mercaptoethanol caused more rapid degradation of the sheath than cyanide or sulfite. Treatment of the sheath with 1 N NaOH resulted in rapid breakdown, while treatment with 1 N HCl resulted in slow but significant hydrolysis. Transmission electron microscopy showed that the 6.5-nm fibrils previously shown to be an integral structural element of the sheath fabric (D. Emerson and W. C. Ghiorse, J. Bacteriol. 175:7808-7818, 1993) were progressively dissociated into random masses during DTT-induced degradation. Quantitation of disulfide bonds with DTT showed that the sheaths contained approximately 2.2 mumol of disulfides per mg of sheath protein. Reaction with 5,5'-dithio-bis-(2-nitrobenzoic acid) showed that sheaths also contained approximately 0.8 mumol of free sulfhydryls per mg of protein. A sulfhydryl-specific fluorescent probe (fluorescein 5-maleimide) showed that the free sulfhydryls in sheathed cell filaments were evenly distributed throughout the sheath. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography of [14C]iodoacetamide-labeled sheaths and DTT-dissociated sheath fibril suspensions showed that the majority of 14C-labeled sulfhydryls in the sheaths did not enter the gel. However, low-molecular-mass silver-staining bands (14 to 45 kDa) did appear in the gels after iodoacetic acid or iodoacetamide alkylation of the dissociated fibrils. These bands did not stain with Coomassie blue. Their migration in gels was slightly affected by digestion with pronase. The fibrils contained 20 to 25% protein. These results confirm that the sheath fibrils consist of high molecular-weight heteropolysaccharide-protein complexes. We hypothesize that proteins in the fibril complexes provide interfibril cross-linking to maintain the structural integrity of the sheath.

Bacterial Proteins↗