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PubMed2007

A new strategy based on recombinant viruses as a tool for assessing drug susceptibility of human immunodeficiency virus type 1.

The emergence of drug-resistant variants during antiretroviral therapy is a serious obstacle to sustained suppression of the human immunodeficiency virus type 1 (HIV-1). For that reason, resistance assays are essential to guide clinicians in the selection of optimal treatment regimens. Genotypic assays are less expensive and results are available faster than phenotypic assays. However, in heavily experienced patients with multiple treatment failures interpretation of complex mutation patterns remains difficult, and in these cases phenotypic assays are recommended. This report describes a novel recombinant virus assay where protease (PR) and reverse transcriptase (RT) sequences derived from the plasma isolated from patients are introduced into the back-bone of an HIV molecular clone that expresses Renilla luciferase protein in the place of nef gene. All drug resistance profiles analyzed correlate with previously reported data and showed high reproducibility. This assay, in addition to a fast (completed in 10 days), precise, reproducible and automated method, presents several advantages as compared to other phenotypic assays. The system described below allows the generation of recombinant viruses with multiples cycles of replication carrying a reporter gene in their genomes. These features increase the sensitivity of the test, an important aspect to be considered in the evaluation of less fit viral isolates. In conclusion, the assay permits the quantitation of the level of resistance of clinical HIV-1 isolates to PR and RT inhibitors.

Animals↗
PubMed1993

Binding of alanine-substituted peptides to the MHC class I protein, Kd.

Peptides eluted from the native MHC class I molecule, Kd, are generally nonamers that display a strong preference for Tyr in position 2. We investigated the molecular basis for this 'consensus motif' by synthesizing a virally derived peptide, NP 147-155, that is known to be presented by Kd on living cells, and peptide variants of NP 147-155 in which the amino acids in the different positions were sequentially replaced by Ala. All of the peptides bound to purified Kd molecules in vitro with high affinity, except for the peptide in which Tyr2 was replaced by Ala, for which the affinity for Kd decreased at least 100-fold. These results confirm the interpretation of the in vivo studies; namely, that Tyr2 is a critical anchor residue for binding to Kd.

Alanine↗
PubMed2026

Osteoarthritis Year in Review 2026: Genetics, genomics and epigenetics.

OBJECTIVE: The purpose of this narrative review is to highlight advances made over the past 12 months in the field of osteoarthritis (OA) genetics, genomics and epigenomics, with a particular focus on the interpretation of OA risk loci through functional genomic and regulatory approaches. DESIGN: PubMed and Europe PMC were searched to identify studies relevant to OA genetics, genomics and epigenomics published between 1st March 2025 and 30th April 2026. Searches used combinations of terms relating to genetics, genomics, epigenomics, functional genomics, molecular quantitative trait loci, chromatin accessibility and enhancer biology. Studies were limited to human subjects and English-language publications, with additional articles identified through citation screening and expert knowledge of the field. RESULTS: Over the past year, the field has continued to transition from large-scale locus discovery towards biological interpretation of OA genetic risk. Major advances included the largest OA genome-wide association study to date, further development of polygenic risk score approaches, and increasing integration of molecular quantitative trait loci, chromatin accessibility, and enhancer biology datasets to prioritise effector genes and elucidate regulatory mechanisms. Several studies highlighted the highly context-dependent nature of OA genetic risk mechanisms, demonstrating that distinct tissues, cell types, and regulatory layers can identify different candidate effector genes at the same locus. Additional developments included increasing application of singlecell and multi-omic technologies to study OA-relevant tissues. CONCLUSION: Recent advances in OA genetics have shifted the field from locus discovery towards mechanistic interpretation. Emerging evidence demonstrates that the biological consequences of genetic variation are highly dependent upon tissue, cell state and disease context, with different functional genomic approaches often prioritising distinct candidate genes and regulatory mechanisms at the same susceptibility locus. Together, these findings suggest that OA risk loci should increasingly be viewed as dynamic regulatory systems rather than simple variant-to-gene relationships, providing a framework for future studies aimed at resolving causal mechanisms, defining disease endotypes, and identifying therapeutic targets.

Genetics↗
PubMed2003

ZZ made EZ: influence of inhibitor configuration on enzyme selectivity.

Selectivity of drug targeting is necessary in order to forestall undesired side-effects. Here, we examine the structural grounds for the configuration-dependent selectivity of 2,7-bis(4-amidinobenzylidene)-cycloheptan-1-one (1) for factor Xa and trypsin: Previous studies showed that factor Xa is preferentially inhibited by the (Z,Z) configuration isomer of (1), whilst trypsin binds equally well to both (E,Z) and (Z,Z) forms. Using engineered trypsin variants, we find similar overall binding modes for the (E,Z) and (Z,Z) isomers. Minor changes in van der Waals' contacts to Tyr99 (Leu in trypsin) explain the differential inhibition of factor Xa. We note differences in the experimental electron densities observed from co-crystallisation and soaking experiments: while the co-crystallisation of (1) with variants containing Tyr99 (Leu99) reveal the exclusive presence of the (Z,Z) ((E,Z)) configurations respectively, soaking experiments with either variant result in mixtures of (E,Z), (Z,Z) and (E,E). This discrepancy arises presumably from differences in the spatial (packing considerations) or chemical (crystallisation conditions) microenvironments. The results presented here represent an extreme example of the problems that face structure-based drug design, in particular the dangers inherent in relying on a single crystal structure for interpreting protein-ligand interactions.

Animals↗
PubMed1996

New serotype of Bartonella henselae in endocarditis and cat-scratch disease.

BACKGROUND: The fastidious nature of Bartonella henselae is such that demonstration of clinical infection relies mainly on serological or molecular biological methods. Only five isolates have been obtained from patients with cat-scratch disease (CSD) and none from endocarditis. METHODS: We isolated B henselae from a CSD patient and, for the first time, from a patient with endocarditis. The isolates were characterised on the basis of morphology, biochemistry, cell-wall fatty-acid analysis, PCR-restriction fragment length polymorphism analysis of the 16-23S intragenic spacer region, and 16S rRNA gene sequences. Characterisation of these isolates indicated them to belong to a new serogroup, which we have called "Marseille", and to a new genotype based on the 16S rRNA gene sequence. The new variant was incorporated into an immuno-fluorescence antibody test (IFAT), which was used to reassess serum samples from 113 CSD patients who were seronegative with the conventional IFAT. FINDINGS: 18 (16%) of these apparently seronegative patients yielded significantly raised titres. 20 CSD patients who were seropositive as judged by the conventional IFAT remained seropositive with the new IFAT. INTERPRETATION: Antigenic variability within the species is one possible reason for inconsistent results in the serological diagnosis of CSD.

Adult↗
PubMed2002

Cryptic lineages in a small frog: the post-glacial history of the spring peeper, Pseudacris crucifer (Anura: Hylidae).

The spring peeper (Pseudacris crucifer) is believed to have been a primary herpetological invader of eastern North America following the most recent period of glacial retreat. We examined the phylogeographic pattern and population structure of P. crucifer to determine whether the distribution of haplotypic variants reflect post-Pleistocene recolonization dynamics. A number of geographically isolated evolutionary lineages were supported by both maximum parsimony and neighbor-joining analyses, and by coalescence approaches applied to mtDNA. South-western Ontario represents a high level of genotypic diversity (pi) due to the presence of two divergent lineages. The geographic distribution of these lineages are interpreted as reflecting post-glacial recolonization dynamics from separate, isolated refugia during the late Pleistocene that have come into secondary contact in SW Ontario. The phylogenetic placement of haplotypes from the range of P. crucifer bartramiana (Florida and South Carolina) does not allow for monophyly of P. crucifer crucifer, and therefore the bartramiana subspecies designation does not reflect a separate evolutionary lineage.

Animals↗
PubMed2026

Polygenic and monogenic adaptation drive evolutionary rescue at different magnitudes of environmental change.

Understanding the genetic basis of rapid adaptation is key to predicting species' evolutionary responses to environmental change. However, it is still debatable whether many small-effect mutations or a few large-effect mutations underlie rapid adaptation, and how this knowledge can predict population survival or extinction. To address this question, we performed a series of ecologically grounded forward-in-time genetic simulations to study rapid adaptation and extinction with increasing magnitudes of environmental change. These simulations were seeded with genomic variation of the plant Arabidopsis thaliana to have a realistic genomic structure, with one (monogenic) to 1,000 (polygenic) variants with varying heritabilities contributing to an environmental adaptive trait. Our results revealed two distinct scenarios of rapid adaptation and population rescue. Under small-to-moderate environmental shifts, high polygenic traits increased evolutionary rescue probability. Under extreme environmental shifts, high polygenic traits lead predictably to extinction, yet monogenic traits sometimes produce one-off winning adaptive genotypes. We interpret our rapid evolutionary rescue findings in terms of the fundamental theorem of natural selection, where trait polygenicity shapes the distribution of genetic variance in fitness across replicates and, in turn, the probability of population survival, with polygenic architectures producing more stable and predictable fitness variance and monogenic architectures generating highly skewed and variable outcomes. These results highlight the insights genomics gives us into the (un)predictability of species' evolutionary responses to global change, with management implications for assisted adaptation and conservation.

Arabidopsis↗
PubMed1995

Genetic polymorphism within HLA-A*02: significant allelic variation revealed in different populations.

HLA-A2 is present at high frequency in most populations, as identified by serological and biochemical means. The value of these methods is limited by their failure to discriminate between the products of the 14 known allelic HLA-A*02 variants. The great majority of genetic polymorphism which defines the allelic variants is found in exons 2 and 3 of the A*02 genes. These exons encode the alpha-1 and alpha-2 domains of the HLA Class I molecules, and variation within the genes may influence the peptide binding specificity of the gene products of each allele. Failure to accurately assign the allelic types has implications in transplantation, in interpretation of cellular assays and in the understanding of HLA disease associations. We have developed a method for determining the 14 known alleles of HLA-A*02 by use of ARMS-PCR to determine the degree of variation of HLA-A*02 alleles in 3 different population groups. Considerable variation was found in the relative frequencies of particular A*02 alleles between Caucasian, oriental and black individuals. Our results indicate the importance of ethnic origin in terms of the expected HLA-A*02 allelic profile, and emphasize the functional significance of allele specific subtyping of HLA-A*02.

Alleles↗
PubMed1976

Serum isoamylases in cystic fibrosis.

Salivary and pancreatic isoamylases were determined in the sera of 33 patients with cystic fibrosis (CF) and in 34 CF-parents. Pancreatic serum isoamylase activities were greatly decreased in patients with CF, and only two values from this group fell within the normal range. Salvary isoamylases, however, were markedly increased so that the total serum amylase activities were normal. We interpret the low pancreatic isoamylase levels in serum to reflect reduced exocrine masses in the pancreas of CF-children. In heterozygotes, the mean activity of the pancreatic isoamylase was significantly higher than in the reference group, while salivary isoamylases were within the normal range. Due to a genetic polymorphism pancreatic isoamylase may occur in two main fractions. This variant type of pancreatic isoamylase appeared more frequently in CF-heterozygotes than was expected from a reference group of blood donors.

Adolescent↗
PubMed2005

Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.

Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

Alternative Splicing↗
PubMed2003

Modeling of flap endonuclease interactions with DNA substrate.

Structure-specific 5' nucleases play an important role in DNA replication and repair uniquely recognizing an overlap flap DNA substrate and processing it into a DNA nick. However, in the absence of a high-resolution structure of the enzyme/DNA complex, the mechanism underlying this recognition and substrate specificity, which is key to the enzyme's function, remains unclear. Here, we propose a three-dimensional model of the structure-specific 5' flap endonuclease from Pyrococcus furiosus in its complex with DNA. The model is based on the known X-ray structure of the enzyme and a variety of biochemical and molecular dynamics (MD) data utilized in the form of distance restraints between the enzyme and the DNA. Contacts between the 5' flap endonuclease and the sugar-phosphate backbone of the overlap flap substrate were identified using enzyme activity assays on substrates with methylphosphonate or 2'-O-methyl substitutions. The enzyme footprint extends two to four base-pairs upstream and eight to nine base-pairs downstream of the cleavage site, thus covering 10-13 base-pairs of duplex DNA. The footprint data are consistent with a model in which the substrate is bound in the DNA-binding groove such that the downstream duplex interacts with the helix-hairpin-helix motif of the enzyme. MD simulations to identify the substrate orientation in this model are consistent with the results of the enzyme activity assays on the methylphosphonate and 2'-O-methyl-modified substrates. To further refine the model, 5' flap endonuclease variants with alanine point substitutions at amino acid residues expected to contact phosphates in the substrate and one deletion mutant were tested in enzyme activity assays on the methylphosphonate-modified substrates. Changes in the enzyme footprint observed for two point mutants, R64A and R94A, and for the deletion mutant in the enzyme's beta(A)/beta(B) region, were interpreted as being the result of specific interactions in the enzyme/DNA complex and were used as distance restraints in MD simulations. The final structure suggests that the substrate's 5' flap interacts with the enzyme's helical arch and that the helix-hairpin-helix motif interacts with the template strand in the downstream duplex eight base-pairs from the cleavage site. This model suggests specific interactions between the 3' end of the upstream oligonucleotide and the enzyme. The proposed structure presents the first detailed description of substrate recognition by structure-specific 5' nucleases.

Base Sequence↗
PubMed1998

Implications of a common polymorphism in intron 12 of the dystrophin gene for deletion detection by multiplex PCR.

The multiplex polymerase chain reaction (PCR) is a reliable and efficient method for detecting dystrophin gene deletions in about 65% of patients with Duchenne or Becker muscular dystrophy (DMD or BMD). The 9-plex PCR assay, which simultaneously amplifies the muscle-specific promoter and exons 3, 6, 13, 43, 47, 50, 52 and 60, is one of the multiplex PCR assays used routinely to test for DMD and BMD deletions. In this study, we describe a previously unrecognized A to G base variation in intron 12 (nt -110 from exon 13) of the dystrophin gene. This variant, located within the annealing site of the exon 13 forward primer, prevented amplification of exon 13 in the 9-plex PCR assay. Present in 56% (25 of 45) of normal Caucasian alleles and 23% (3 of 13) of normal black American alleles, it is likely encountered frequently during dystrophin deletion analysis by multiplex PCR, and may complicate test result interpretation. Therefore, we suggest two modifications for the multiplex PCR detection of dystrophin gene deletion.

Alleles↗
PubMed1997

Microscopic pKa values of Escherichia coli thioredoxin.

Thiol:disulfide oxidoreductases have a CXXC motif within their active sites. To initiate the reduction of a substrate disulfide bond, the thiolate form of the N-terminal cysteine residue (CXXC) of this motif performs a nucleophilic attack. Escherichia coli thioredoxin [Trx (CGPC)] is the best characterized thiol:disulfide oxidoreductase. Previous determinations of the active-site pKa values of Trx have led to conflicting interpretations. Here, 13C-NMR spectroscopy, site-specific isotopic labeling, and site-directed mutagenesis were used to demonstrate that analysis of the titration behavior of wild-type Trx requires the invocation of microscopic pKa values for two interacting active-site residues: Asp26 (7.5 and 9.2) and Cys32 (CXXC; 7.5 and 9.2). By contrast, in two Trx variants, D26N Trx and D26L Trx, Cys32 exhibits a pKa near 7.5 and has a well-defined, single-pKa titration curve. Similarly, in oxidized wild-type Trx, Asp26 has a pKa near 7.5. In CVWC and CWGC Trx, Cys32 exhibits a single pKa near 6.2. In all five enzymes studied here, there is no evidence for a Cys35 (CXXC) pKa of < 11. This study demonstrates that a comprehensive approach must be used to unravel complex titration behavior of the functional groups in a protein.

Acids↗
PubMedDate not supplied

Multilobated large B-cell lymphoma diagnosed cytologically. A case report.

BACKGROUND: Fine needle aspiration (FNA) biopsy can be used to reliably classify most conditions involving lymph nodes or, at least, significantly reduce the differential diagnosis. CASE: A 70-year-old male presented with an ulcerated mass arising from the left tonsillar fossa and involving the anterior and posterior pillars. A biopsy of the tonsillar mass performed at an outside hospital was interpreted as a large cell undifferentiated carcinoma. Subsequently the patient developed systemic lymphadenopathy. A bone scan showed intense uptake within the medial tibial plateau of the left knee. FNA biopsy of the right axillary mass was interpreted at University of Cincinnati Medical College as a large cell lymphoma, multilobated type. Histologic and immunohistochemical studies of the lymph node confirmed the presence of multilobated B-cell lymphoma. Lymphoma chemotherapy was initially successful but was discontinued due to toxicity. The patient died two months after the initial cytologic diagnosis of lymphoma. CONCLUSION: Multilobated lymphomas are an unusual variant of non-Hodgkin's lymphomas (mostly B-cell type). Cytology and immunocytochemistry are useful diagnostic procedures that can help to diagnose this relatively uncommon type of lymphoma and significantly reduce the possibility of misdiagnosis.

Aged↗
PubMed2005

PfEMP1 expression is reduced on the surface of knobless Plasmodium falciparum infected erythrocytes.

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a key virulence factor for this species of human malarial parasite. PfEMP1 is expressed on the surface of infected erythrocytes (IEs) and directly mediates adhesion to a variety of host cells. A number of other parasite-encoded proteins are similarly exported to the IE plasma membrane and play an indirect role in this adhesion process through the modification of the erythrocyte cytoskeleton and the formation of electron dense knobs into which PfEMP1 is anchored. Analysis of the specific contribution of knob-associated proteins to adhesion is difficult due to rapid PfEMP1 switching during in vitro culture. Furthermore, these studies typically assume that the level and distribution of PfEMP1 exposed in knobby (K(+)) and knobless (K(-)) IEs is unaltered, an assumption not yet supported with data. We describe here the preparation and characterisation of a panel of isogenic K(+) and K(-) parasite clones that express one of two defined PfEMP1 variants. Analysis of the cytoadhesive properties of these clones shows that both static and flow adhesion is reduced in all the K(-) clones and, further, that this correlates with an approximately 50% reduction in PfEMP1 displayed on the IE surface. However, despite this reduction, the gross distribution of PfEMP1 in K(-) IEs appears unaltered. These data impact on our current interpretation of the role of knobs in adhesion and the mechanism of trafficking PfEMP1 to the IE surface.

Animals↗
PubMed1998

[Extrafollicular variant of centrally located adenomatoid odontogenic tumor].

An adenomatoid odontogenic tumor has been reported which was not connected with any impacted or displaced tooth. The clinical and radiographical results were consistent with a non-odontogenic cyst, but in this case the pathohistological examination revealed string-like and partly cross-linked cells of odontogenic epithelium as well as solid aggregates of epithelia, possessing gland-like structures at their centers. Furthermore, small deposits of PAS-positive materials could be seen which could be interpreted as non-mineralized dentine with a tubular basic structure. The therapy consisted of completely enucleating the tumor. Any recurrence of malignant degeneration has not yet been reported.

Adult↗
PubMed2001

Clinicopathologic variants of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinomas (SCC) are one of the most common malignancies, which, with early recognition, may be curable. These tumors represent a broad spectrum of disorders with many significant clinical, morphologic, and etiologic distinctions. The objective of this article is to review the important clinicopathologic features of SCC with particular emphasis on important recent developments, practical application, and their relevance to the practice of pathology. The most pertinent literature of the last 5 years was reviewed and capsulized. Appropriate histologic interpretation and clinical management of patients with cutaneous SCC requires a comprehensive understanding of the latest advances in the broad field of dermatopathology. Squamous cell carcinoma of the skin represents a complex group of disease subtypes, each with its own characteristics, which may influence morphologic diagnosis as well as treatment and clinical management.

Carcinoma, Squamous Cell↗
PubMed1985

Polymorphism of human C2 detected by immunoblotting.

To allotype human complement component C2, thin layer agarose gel isoelectric focusing of human serum and/or EDTA-plasma was performed followed by direct immunofixation or by immunoblotting with a specific anti-human-C2 antibody. Using reference samples for C2 BC phenotypes and local samples from an HLA, C4, and Bf genotyped family, a differentiation of the C2*B and C2*C variants segregating with the respective HLA haplotype was achieved. The C2 BC phenotype is characterized by a double banding pattern similar to that observed in the haemolytic overlay assay usually used for the detection of C2 polymorphism. An homozygous C2*Q0 reference sample determined by functional assays was shown to be biochemically deficient, as demonstrated by immunofixation and immunoblotting. The visual interpretation of C2 phenotypes was definitely easier after immunofixation and immunoblotting than after an haemolytic overlay assay. In addition, the method for C2 allotyping described here has several advantages, in particular it saves time and tolerates repeated thawing and freezing of the samples.

Complement C2↗