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At least 1,693 records · Page 94Linked to original sources
PubMed1991

Breast-conserving treatment or mastectomy in early breast cancer: a clinical decision analysis with special reference to the risk of local recurrence.

A clinical decision analysis was performed to judge the impact of local recurrences after breast-conserving treatment (BCT) on the (quality-adjusted) life expectancy of breast cancer patients. A life-long follow-up of two patient groups, one of which had undergone mastectomy and one BCT, was simulated by a Markov model of medical prognosis. Data used in the model originated from the literature. Since results in the source papers were not split according to stage, we performed two analyses: one with data from all source studies (T1 and T2) and one with data from source studies, concerning only T1 patients. In both analyses, the conclusion was that BCT yields better quality-adjusted life expectancy than mastectomy. Sensitivity analysis, however, identified subgroups of patients who should preferably undergo mastectomy. These subgroups are: patients preferring mastectomy to BCT, patients with a high risk of local recurrence, young patients and patients at high age, if they also have a high local recurrence risk. For these groups, patient preferences should play a major role in recommending treatment.

Adult↗
PubMed2025

Identification and classification of ion-channels across the tree of life provide functional insights into understudied CALHM channels.

The ion channel (IC) genes encoded in the human genome play fundamental roles in cellular functions and disease and are one of the largest classes of druggable proteins. However, limited knowledge of the diverse molecular and cellular functions carried out by ICs presents a major bottleneck in developing selective chemical probes for modulating their functions in disease states. The wealth of sequence data available on ICs from diverse organisms provides a valuable source of untapped information for illuminating the unique modes of channel regulation and functional specialization. However, the extensive diversification of IC sequences and the lack of a unified resource present a challenge in effectively using existing data for IC research. Here, we perform integrative mining of available sequence, structure, and functional data on 419 human ICs across disparate sources, including extensive literature mining by leveraging advances in large language models to annotate and curate the full complement of the "channelome". We employ a well-established orthology inference approach to identify and extend the IC orthologs across diverse organisms to above 48,000. We show that the depth of conservation and taxonomic representation of IC sequences can further be translated to functional similarities by clustering them into functionally relevant groups, which can be used for downstream functional prediction on understudied members. We demonstrate this by delineating co-conserved patterns characteristic of the understudied family of the Calcium Homeostasis Modulator (CALHM) family of ICs. Through mutational analysis of co-conserved residues altered in human diseases and electrophysiological studies, we show that these evolutionarily-constrained residues play an important role in channel gating functions. Thus, by providing new tools and resources for performing large comparative analyses on ICs, this study addresses the unique needs of the IC community and provides the groundwork for accelerating the functional characterization of dark channels for therapeutic intervention.

CALHM1↗
PubMed1986

Lambda phage protein Nu 1 contains the conserved DNA binding fold of repressors.

Analysis of 64 lambda phage proteins revealed the presence of four strong variants of the conserved DNA binding fold of repressors. Three of them have been known from previous studies but the Nu 1 gene product is a new member of the family of proteins that may bind strongly to DNA in the repressor-like fashion. It is peculiar that the motif occurs in the very N terminus of Nu 1 just between two possible starts of its gene.

Amino Acid Sequence↗
PubMed2005

Mimivirus gene promoters exhibit an unprecedented conservation among all eukaryotes.

The initial analysis of the recently sequenced genome of Acanthamoeba polyphaga Mimivirus, the largest known double-stranded DNA virus, predicted a proteome of size and complexity more akin to small parasitic bacteria than to other nucleocytoplasmic large DNA viruses and identified numerous functions never before described in a virus. It has been proposed that the Mimivirus lineage could have emerged before the individualization of cellular organisms from the three domains of life. An exhaustive in silico analysis of the noncoding moiety of all known viral genomes now uncovers the unprecedented perfect conservation of an AAAATTGA motif in close to 50% of the Mimivirus genes. This motif preferentially occurs in genes transcribed from the predicted leading strand and is associated with functions required early in the viral infectious cycle, such as transcription and protein translation. A comparison with the known promoter of unicellular eukaryotes, amoebal protists in particular, strongly suggests that the AAAATTGA motif is the structural equivalent of the TATA box core promoter element. This element is specific to the Mimivirus lineage and may correspond to an ancestral promoter structure predating the radiation of the eukaryotic kingdoms. This unprecedented conservation of core promoter regions is another exceptional feature of Mimivirus that again raises the question of its evolutionary origin.

Base Sequence↗
PubMed2004

Extreme conservation of noncoding DNA near HoxD complex of vertebrates.

BACKGROUND: Homeotic gene complexes determine the anterior-posterior body axis in animals. The expression pattern and function of hox genes along this axis is colinear with the order in which they are organized in the complex. This 'chromosomal organization and functional correspondence' is conserved in all bilaterians investigated. Genomic sequences covering the HoxD complex from several vertebrate species are now available. This offers a comparative genomics approach to identify conserved regions linked to this complex. Although the molecular basis of 'colinearity' of Hox complexes is not yet understood, it is possible that there are control elements within or in the proximity of these complexes that establish and maintain the expression patterns of hox genes in a coordinated fashion. RESULTS: We have compared DNA sequence flanking the HoxD complex of several primate, rodent and fish species. This analysis revealed an unprecedented conservation of non-coding DNA sequences adjacent to the HoxD complex from fish to human. Stretches of hundreds of base pairs in a 7 kb region, upstream of HoxD complex, show 100% conservation across the vertebrate species. Using PCR primers from the human sequence, these conserved regions could be amplified from other vertebrate species, including other mammals, birds, reptiles, amphibians and fish. Our analysis of these sequences also indicates that starting from the conserved core regions, more sequences have been added on and maintained during evolution from fish to human. CONCLUSION: Such a high degree of conservation in the core regions of this 7 kb DNA, where no variation occurred during approximately 500 million years of evolution, suggests critical function for these sequences. We suggest that such sequences are likely to provide molecular handle to gain insight into the evolution and mechanism of regulation of associated gene complexes.

Animals↗
PubMed2005

Mutagenesis analysis of the serotonin 5-HT2C receptor and a Caenorhabditis elegans 5-HT2 homologue: conserved residues of helix 4 and helix 7 contribute to agonist-dependent activation of 5-HT2 receptors.

An alignment of serotonin [5-hydroxytryptamine (5-HT)] G protein-coupled receptors identified a lysine at position 4.45 (helix 4) and a small polar residue (serine or cysteine) at 7.45 (helix 7) that occur exclusively in the 5-HT2 receptor family. Other serotonin receptors have a hydrophobic amino acid, typically a methionine, at 4.45 and an invariant asparagine at 7.45. The functional significance of these class-specific substitutions was tested by site-directed mutagenesis of two distantly related 5-HT2 receptors, Caenorhabditis elegans 5-HT2ce and rat 5-HT2C. Residues 4.45 and 7.45 were each mutated to a methionine and asparagine, respectively, or an alanine and the resulting constructs were tested for activity. A K4.45M mutation decreased serotonin-dependent activity (Emax) of the rat 5-HT2C receptor by 60% and that of the C. elegans homologue by 40%, as determined by a fluorometric plate-based calcium assay. The rat mutant also exhibited nearly sixfold higher agonist binding affinity and significantly lower constitutive activity compared with wildtype. Mutagenesis of S7.45 in the C. elegans receptor increased serotonin binding affinity by up to 25-fold and decreased Emax by up to 65%. The same mutations of the cognate C7.45 in rat 5-HT2C produced a smaller fourfold change in the affinity for serotonin and decreased agonist efficacy by up to 50%. Substitutions of S/C7.45 did not produce a significant change in the basal activity of either receptor. All mutants tested exhibited levels of receptor expression similar to the corresponding wildtype based on measurements of specific [3H]-mesulergine binding or flow cytometry analyses. Taken together, these results suggest that K4.45 and S/C7.45 play an important role in the conformational rearrangements leading to agonist-induced activation of 5-HT2 receptors.

Amino Acid Sequence↗
PubMed1991

Role of conserved proline residues in stabilizing tryptophan synthase alpha subunit: analysis by mutants with alanine or glycine.

To study the role of Pro residues in the conformation and conformational stability of a protein, nine mutant alpha subunits of tryptophan synthase from Escherichia coli, in which Ala or Gly was substituted for each of six Pro residues (positions 28, 57, 62, 96, 132, and 207) that are conserved in 10 microorganisms, were constructed by means of site-directed mutagenesis. The far-ultraviolet (UV) CD spectra of five mutant alpha subunits with Ala in place of Pro were identical to the spectrum of the wild-type protein, the exception being the mutant at position 207 (P207A). CD values in the far-UV region were less negative for P207A, indicating that the Pro residue at position 207 plays a role in maintaining the intact structure of the alpha subunit. The negative CD values of the Gly mutants examined (P28G, P96G, and P132G) were also decreased. Calorimetric measurements showed that the two mutants at position 28 (P28G and P28A) gave two peaks in the excess heat capacity curve, whereas the wild type and other Pro mutants had only a single peak. The stability of each mutant protein relative to that of the wild type was about the same for P57A, less for P62A and P132A, and markedly decreased for P96A and P207A, which are substituted at less mobile positions. The changes of denaturation entropy (delta delta dS) at the denaturation temperature of the wild-type protein (54.1 degrees C at pH 9.0) were positive for P57A, P62A, and P132A, but negative for P96A, P207A, and P132G.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1997

Amino acid substitutions preserve protein folding by conserving steric and hydrophobicity properties.

We present a comprehensive analysis of amino acid substitution patterns (sets of residues in a position of a multiple alignment) and conservation of physicochemical properties in alignments of protein sequences. Of the one million possible substitution patterns, only a few hundred account for the majority of aligned positions. Very similar distributions of substitution patterns are observed in all but one of the diverse databases of multiple alignments. In these substitution patterns we analyzed the conservation of 511 physicochemical and steric amino acid properties. Highest conservation was observed in those steric and transfer free energy-related properties that are crucial for folding. The best conserved steric properties include the minimal width of the side chains and their interactions with other residues. Among the hydrophobicity-related properties, charge and those properties that provide information on propensities to form secondary structures or side chain conformation, appear to be better conserved than pure hydrophobicity measures. Physicochemical sequence analysis based on the most conserved properties is expected to aid searching a protein sequence query against a database of multiple alignments, prediction of secondary and tertiary structures and protein engineering.

Amino Acids↗
PubMed2002

The left-right determinant inversin has highly conserved ankyrin repeat and IQ domains and interacts with calmodulin.

All vertebrates have a left-right body axis with invariant asymmetries of the heart and the positions of the abdominal viscera. Major advances have recently been made in defining molecular components of the pathway specifying the vertebrate left-right axis, but our knowledge of the early determinants is extremely limited. In the invmouse the left-right axis is consistently reversed, unlike other vertebrate mutants where randomisation of situs is apparent. The gene disrupted in this mouse encodes a 1062-amino-acid protein, inversin. We previously reported 16 tandem ankyrin repeats, spanning amino acids 13-557, and two putative nuclear localisation sequences, but otherwise the sequence offered few clues to the possible function. In order to identify regions likely to be functionally important, we have identified and characterised orthologous sequences in several species, including chick, Xenopus and zebrafish. Sequence comparisons show strong conservation of the ankyrin repeat region and also a lysine-rich domain spanning amino acids 558-604. Further analysis identified a highly conserved IQ calmodulin-binding domain in the latter region and another such domain in an otherwise poorly conserved C-terminal region. A yeast two-hybrid screen identified calmodulin in one third of the positive clones, and we confirmed this interaction by immunoprecipitation.

Amino Acid Sequence↗
PubMed1993

Topology, structure and evolution of two families of proteins involved in antibiotic and antiseptic resistance in eukaryotes and prokaryotes--an analysis.

Analysis of deduced amino acid sequences has demonstrated that the sequences of eukaryotic and prokaryotic proteins mediating resistance to antibiotics and antiseptics are highly related. Hydropathy analysis and alignment of conserved motifs revealed that these proteins can be divided into two separate families with either 12 or 14 transmembrane segments (TMS). Conserved motifs have been identified which are either characteristic for each family or conserved in both families. The conservation of these motifs suggested that they may be essential for the function of these proteins. Phylogenetic and structural analysis revealed that the two families may have evolved from a common ancestor with six TMS.

Amino Acid Sequence↗
PubMed2000

Factors associated with the development of recurrent acute otitis media--the significance of choosing the right and accurate dependent and independent variables in the multivariate analysis.

The results of univariate and multivariate statistical analysis were compared in identifying predictive factors of the development of recurrent acuta otitis media (RAOM) after an initial episode of acute otitis media (AOM) in 121 children. Univariate correlations between the development of RAOM and potential risk factors were analysed, and variables at p < 0.10 were incorporated into the stepwise multiple logistic regression analysis. The comparisons between the univariate and multivariate analysis in identifying the predictive factors were made and the importance of changing the dependent variables in the multivariate analysis was analysed. It seems that univariate analysis is over-sensitive, but multivariate analysis is over-conservative in finding possible predictors of RAOM. Choosing the right and accurate dependent and independent variables in the multivariate analysis is extremely important, when this method is used.

Acute Disease↗
PubMed1992

Expression of the Na-Ca exchanger in diverse tissues: a study using the cloned human cardiac Na-Ca exchanger.

In many cells including cardiac myocytes, cytoplasmic Ca is importantly controlled by the plasmalemmal Na-Ca exchanger (3, 8). The tissue diversity and differences in cellular environment raise the question whether the same exchanger is found in all tissues. Recent experiments using rod cells have demonstrated that at least two forms of Na-dependent Ca transport exist. We have examined this issue in various rat and human tissues using the cloned human cardiac Na-Ca exchanger cDNA. Northern blot analysis in these two species show that the major transcript of the Na-Ca exchanger is 7.2 kilobases in heart, brain, kidney, liver, pancreas, skeletal muscle, placenta, and lung. Furthermore, ribonuclease protection analysis in rats shows conservation of the 348-base pair segment tested in heart, brain, kidney, skeletal muscle, and liver. Additionally, Southern blot analysis suggests that a single gene encodes this Na-Ca exchanger. Finally, we show that the clone used to generate our probes encodes a completely functional Na-Ca exchanger. With the use of COS cells and 293 cells transfected with the cloned human cardiac Na-Ca exchanger, we tested the Ca transport properties of the Na-Ca exchanger, the voltage dependence of the Na-Ca exchanger, as well as the Na dependence of the transport function of the Na-Ca exchanger. We conclude that the cardiac form of the Na-Ca exchanger is completely functional when the cDNA is expressed in mammalian cell lines, and, furthermore, this "cardiac" form of the Na-Ca exchanger is naturally expressed in all human and rat tissues tested (but at varying levels).

Amino Acid Sequence↗
PubMed2004

Identification of critical residues of choline kinase A2 from Caenorhabditis elegans.

Choline kinase catalyzes the phosphorylation of choline by ATP, the first committed step in the CDP-choline pathway for phosphatidylcholine biosynthesis. To begin to elucidate the mechanism of catalysis by this enzyme, choline kinase A-2 from Caenorhabditis elegans was analyzed by systematic mutagenesis of highly conserved residues followed by analysis of kinetic and structural parameters. Specifically, mutants were analyzed with respect to K(m) and k(cat) values for each substrate and Mg(2+), inhibitory constants for Mg(2+) and Ca(2+), secondary structure as monitored by circular dichroism, and sensitivity to unfolding in guanidinium hydrochloride. The most severe impairment of catalysis occurred with the modification of Asp-255 and Asn-260, which are located in the conserved Brenner's phosphotransferase motif, and Asp-301 and Glu-303, in the signature choline kinase motif. For example, mutation of Asp-255 or Asp-301 to Ala eliminated detectable catalytic activity, and mutation of Asn-260 and Glu-303 to Ala decreased k(cat) by 300- and 10-fold, respectively. Additionally, the K(m) for Mg(2+) for mutants N260A and E303A was approximately 30-fold higher than that of wild type. Several other residues (Ser-86, Arg-111, Glu-125, and Trp-387) were identified as being important: Catalytic efficiencies (k(cat)/K(m)) for the enzymes in which these residues were mutated to Ala were reduced to 2-25% of wild type. The high degree of structural similarity among choline kinase A-2, aminoglycoside phosphotransferases, and protein kinases, together with the results from this mutational analysis, indicates it is likely that these conserved residues are located at the catalytic core of choline kinase.

Adenosine Triphosphate↗
PubMed1996

Mammographic features after conservation therapy for malignant breast disease: serial findings standardized by regression analysis.

OBJECTIVE: The purpose of this study was to determine the incidence and natural history of mammographic changes in patients within 5 years of conservation therapy for malignant breast disease. MATERIALS AND METHODS: We reviewed the records of 164 consecutive patients with a history of conservation therapy for malignant disease. We recorded mammographic changes related to treatment for each year after surgery. Linear regression analysis was applied to determine trends for progression, regression, or stability of findings. RESULTS: We evaluated 158 patients with 162 lesions for which initial mammographic evaluation had occurred within 5 years of surgery. Of these 158 patients, 121 (77%) underwent serial studies. A total of 152 patients (96%) showed changes on mammograms that represented scarring, usually in multiple locations. Findings at initial evaluation included architectural distortion (n = 110; 82%), increased regional density or scarring (n = 106; 79%), skin thickening (n = 73; 54%), masses (n = 16; 12%), and calcifications (n = 4; 3%). All findings except calcifications showed partial resolution over time, with architectural distortion showing the most significant resolution (p = .05). CONCLUSION: Mammographic features after conservation therapy for breast cancer are common at 1 year after treatment. With the exception of calcifications, we found that all changes showed decreased prominence during the next 5 years. Recognition of such trends during routine surveillance should facilitate the early identification of changes that represent recurrence or do novo malignancy.

Adult↗
PubMed1986

The results of early conservative and surgical treatment of cervical spinal cord injured patients.

The paper presents the analysis of the results of treatment of 1180 patients with traumatic injury of cervical spinal cord, admitted to hospital within the first hours or days after injury. The analysis of the results of conservative (632 patients) and surgical treatment (548 patients) has shown that the results are to a large extent dependent on the time of commencement of specialistic treatment.

Humans↗
PubMed2002

Conservative medical therapy of infections following osteosynthesis: a retrospective analysis of a six-year experience.

The conventional therapeutic approach to bone infection associated with osteosynthesis is based on the idea that microbial eradication is most readily achieved by removal of the foreign material together with adequate antimicrobial therapy. This strategy usually requires implantation of external fixation devices with additional discomfort to the patient. We report our experience with conservative medical and antimicrobial therapy without removal of the osteosynthesis until adequate bone callus deposition is documented by bone radiography scan. Twenty patients with infections associated with intramedullary nailing (9 patients), screws and plate (9 patients) or screws (2 patients) were treated between 1995 to 2000. Osteosynthesis implantation sites were tibia (7 patients), femur (6 patients), femur and tibia (1 patient), humerus (1 patient), others (5 patients). Diagnosis of infection was based on clinical-microbiological evidence and confirmed by 99Tc-labeled leukocyte scan studies. Offending pathogens were Staphylococcus aureus 17 cases, Staphylococcus aureus + Escherichia coli, Staphylococcus epidermidis, unknown, 1 case each. Most infections were initially treated with intravenous or intramuscular teicoplanin +/- ciprofloxacin or rifampin followed by oral antimicrobial therapy usually with ciprofloxacin or minocycline plus rifampin. Mean duration of antimicrobial therapy was 27.7 weeks (range 12-64 weeks). All patients (100%) were cured, and none complained of side-effects requiring antibiotic therapy discontinuation. We conclude that conservative medical therapy is feasible for osteosynthesis-associated bone infection.

Adolescent↗
PubMed2004

MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism.

Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study.

3' Untranslated Regions↗
PubMed1995

Lack of genetically determined structural variants of the human serotonin-1E (5-HT1E) receptor protein points to its evolutionary conservation.

Using single strand conformational analysis, we screened the complete coding sequence of the serotonin-1E (5-HT1E) receptor gene for the presence of DNA sequence variation in a sample of 157 unrelated individuals. We detected only a silent C-->T transition at the third position of codon 177. The lack of significant mutations leading to structural variants of the human 5-HT1E receptor protein points to a high evolutionary conservation of this receptor protein.

Base Sequence↗