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At least 379 records · Page 21Linked to original sources
PubMed2000

Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features.

Normal development of the kidney is a highly complex process that requires precise orchestration of proliferation, differentiation, and apoptosis. In the past few years, a number of genes that regulate these processes, and hence play pivotal roles in kidney development, have been identified. The Wilms' tumor suppressor gene WT1 has been shown to be one of these essential regulators of kidney development, and mutations in this gene result in the formation of tumors and developmental abnormalities such as the Denys-Drash and Frasier syndromes. A fascinating aspect of the WT1 gene is the multitude of isoforms produced from its genomic locus. In this review, our current understanding of the structural features of WT1, how they modulate the transcriptional and post-transcriptional activities of the protein, and how mutations affecting individual isoforms can lead to diseased kidneys is summarized. In addition, results from transgenic experiments, which have yielded important findings regarding the function of WT1 in vivo, are discussed. Finally, data on the unusual feature of RNA editing of WT1 transcripts are presented, and the relevance of RNA editing for the normal functioning of the WT1 protein in the kidney is discussed.

Animals↗
PubMed2001

Beyond the electronic textbook model: software techniques to make on-line educational content dynamic.

OBJECTIVE: We describe a working software technology that enables educators to incorporate their expertise and teaching style into highly interactive and Socratic educational material for distribution on the world wide web. MATERIALS/METHODS: A graphically oriented interactive authoring system was developed to enable the computer novice to create and store within a database his or her domain expertise in the form of electronic knowledge. The authoring system supports and facilitates the input and integration of several types of content, including free-form, stylized text, miniature and full-sized images, audio, and interactive questions with immediate feedback. The system enables the choreography and sequencing of these entities for display within a web page as well as the sequencing of entire web pages within a case-based or thematic presentation. Images or segments of text can be hyperlinked with point-and-click to other entities such as adjunctive web pages, audio, or other images, cases, or electronic chapters. Miniature (thumbnail) images are automatically linked to their full-sized counterparts. The authoring system contains a graphically oriented word processor, an image editor, and capabilities to automatically invoke and use external image-editing software such as Photoshop. The system works in both local area network (LAN) and internet-centric environments. An internal metalanguage (invisible to the author but stored with the content) was invented to represent the choreographic directives that specify the interactive delivery of the content on the world wide web. A database schema was developed to objectify and store both this electronic knowledge and its associated choreographic metalanguage. A database engine was combined with page-rendering algorithms in order to retrieve content from the database and deliver it on the web in a Socratic style, assess the recipient's current fund of knowledge, and provide immediate feedback, thus stimulating in-person interaction with a human expert. RESULTS: This technology enables the educator to choreograph a stylized, interactive delivery of his or her message using multimedia components assembled in virtually any order, spanning any number of web pages for a given case or theme. An educator can thus exercise precise influence on specific learning objectives, embody his or her personal teaching style within the content, and ultimately enhance its educational impact. CONCLUSION: The described technology amplifies the efforts of the educator and provides a more dynamic and enriching learning environment for web-based education.

Computer-Assisted Instruction↗
PubMed1999

The role of tapasin in MHC class I antigen assembly.

The discovery of tapasin has shed new light on the mechanisms of major histocompatibility complex (MHC) class I assembly in the endoplasmic reticulum (ER). Tapasin appears to play an important role in the stable assembly of class I molecules with peptide, however, the precise function of tapasin remains elusive. The pursuit of tapasin function is complicated by the observation that tapasin is not required for successful antigen presentation by all class I molecules. In addition, current data suggest that the putative role of tapasin as a bridging molecule between transporter associated with antigen presentation (TAP) and class I is only of minor importance in tapasin action, and tapasin' s major role appears to be as an active cofactor in the assembly of class I. Furthermore, it is clear that class I molecules can follow multiple pathways for successful assembly in the ER. These pathways may or may not include the interaction of class I molecules with the accessory proteins tapasin, calreticulin, ERp57, or TAP. I would like to suggest that the particular pathway utilized by a given class I molecule depends more upon the availability of appropriate peptides rather than on an intrinsic property of the class I molecule, and that tapasin may serve a peptide editing function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Prime-sight and blindsight.

Listening to subject's commentaries can be a useful spur to novel scientific departures, as in studies of blindsight. Recently further testing (after a gap of 17 years) has been possible with subject DB, who was a blindsight patient (the first) tested intensively over a period of 10 years and who was the subject of the book, (Blindsight OUP, 1986, 2nd edition, 1998). Essentially his original capacity is the same or somewhat more sensitive. Some further types of discriminations have now been tested that were not possible in the original study. But a new feature was discovered, namely that he describes conscious after-images of a wide range of inducing stimuli of which he is unconscious. The properties of the after-images are briefly described, such as their occurrence following unseen colour patches, luminance changes, shape, spatial frequency, their long durations, showing inter-ocular transfer, as well as their conforming to Emmert's Law. Various approaches are discussed towards finding the source of their generation, such as the use of after-images of colour mixes of separate inputs to the two eyes ("cortical yellow"). They are also discussed in terms of after-images in normal subjects that are generated by imagination. The discovery offers a rare potential opportunity to compare the brain activity associated with both the conscious and unconscious attributes of the precisely the same stimuli in the same locus in the same subject.

Adult↗
PubMed1997

Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus.

The anti-DNA response is a hallmark of systemic lupus erythematosus (SLE). The precise mechanisms leading to anti-DNA antibody (Ab) production remain to be studied. Nonetheless, it is becoming clear that anti-DNA Abs cause inflammatory lesions not only via deposition of circulating immune complexes (IC) consisting of anti-DNA Ab and antigens (Ags), but also via in situ IC formation by cationic anti-DNA Abs. It is intriguing that cationic anti-DNA Abs are encoded by a unique germline Vkappa gene, A30, which encodes an extraordinary cationic light chain, whereas somatic mutations did not induce a cationic shift of electrical charge in human lupus nephritis, suggesting that the usage of a specific germline gene may confer the cationic charge (or pathogenicity) on anti-DNA Abs and that somatic mutations induce the affinity maturation of Abs. Whether cationic anti-DNA Abs will develop depends at least partly on the presence or absence of the germline A30 gene, since patients who lack this gene in the germline Vkappa repertoire did not develop severe lupus nephritis. Receptor editing, a mechanism for changing the affinity of the B cell Ag receptor [surface immunoglobulin (Ig) receptor] to avoid self-reactivity actually seems defective in patients with SLE because normal B cells edited the A30 gene, whereas SLE B cells express A30 mRNA. Thus, along with the importance of somatic mutations, polymorphisms of Ig Vkappa locus, and genetic predisposition, the failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.

Antibodies, Antinuclear↗
PubMed2003

Human fibrillarin forms a sub-complex with splicing factor 2-associated p32, protein arginine methyltransferases, and tubulins alpha 3 and beta 1 that is independent of its association with preribosomal ribonucleoprotein complexes.

Fibrillarin (FIB, Nop1p in yeast) is an RNA methyltransferase found not only in the fibrillar region of the nucleolus but also in Cajal bodies. FIB is essential for efficient processing of preribosomal RNA during ribosome biogenesis, although its precise function in this process and its role in Cajal bodies remain uncertain. Here, we demonstrate that the human FIB N-terminal glycine- and arginine-rich domain (residues 1-77) and its spacer region 1 (78-132) interact with splicing factor 2-associated p32 (SF2A-p32) and that the FIB methyltransferase-like domain (133-321) interacts with protein-arginine methyltransferase 5 (PRMT5, Janus kinase-binding protein 1). We also show that these proteins associate with several additional proteins, including PRMT1, tubulin alpha 3, and tubulin beta 1 to form a sub-complex that is principally independent of the association of FIB with preribosomal ribonucleoprotein complexes that co-immunoprecipitate with the sub-complex in human cells expressing FLAG-tagged FIB. Based on the physical association of FIB with SF2A-p32 and PRMTs, as well as the other reported results, we propose that FIB may coordinate both RNA and protein methylation during the processes of ribosome biogenesis in the nucleolus and RNA editing such as small nuclear (nucleolar) ribonucleoprotein biogenesis in Cajal bodies.

Chromosomal Proteins, Non-Histone↗
PubMed1990

An interactive treatment planning system for ophthalmic plaque radiotherapy.

Brachytherapy using removable episcleral plaques containing sealed radioisotope sources is being studied as an alternative to enucleation in the treatment of choroidal melanoma and other tumors of the eye. Encouraging early results have been reported, but late complications which lead to loss of vision continue to be a problem. A randomized national study, the Collaborative Ocular Melanoma Study (COMS) is currently in progress to evaluate the procedure. The COMS specified isotope is 125I. Precise dosimetric calculations near the plaque may correlate strongly with complications and could also be used to optimize isotope loading patterns in the plaques. A microcomputer based treatment planning system has been developed for ophthalmic plaque brachytherapy. The program incorporates an interactive, 3-dimensional, solid-surface, color-graphic interface. The program currently supports 125I and 192Ir seeds which are treated as anisotropic line sources. Collimation effects related to plaque structure are accounted for, permitting detailed study of shielding effectiveness near the lip of a plaque. A dose distribution matrix may be calculated in any subregion of a transverse, sagittal, or coronal planar cross section of the eye, in any plane transecting the plaque and crossing the eye diametrically, or on a spherical surface within or surrounding the eye. Spherical surfaces may be displayed as 3-dimensional perspective projections or as funduscopic diagrams. Isodose contours are interpolated from the dose matrix. A pointer is also available to explicitly calculate and display dose at any location on the dosimetry surface. An interactive editing capability allows new plaque designs to be rapidly added to the system.

Brachytherapy↗
PubMed2025

A comprehensive review of genomic-scale genetic engineering as a strategy to improve bacterial productivity.

Bacterial genome engineering has evolved to provide increasingly precise, robust and rapid tools, driving the development and optimization of bacterial production of numerous compounds. The field has progressed from early random mutagenesis methods, labour-intensive and inefficient, to rational and multiplexed strategies enabled by advances in genomics and synthetic biology. Among these tools, CRISPR/Cas has stood out for its versatility and its ability to achieve precision levels ranging from 50% to 90%, compared to the 10-40% obtained with earlier techniques, thereby enabling remarkable improvements in bacterial productivity. Nevertheless, like its predecessors, it still demands continuous refinement to reach full maturity. In this context, the present review addresses the lack of a unified overview by summarizing historical milestones and practical applications of genomic engineering tools in bacteria. It integrates diverse approaches to provide a comprehensive perspective on the evolution and prospects of these fundamental biotechnological tools.

Bacteria↗
PubMed2025

Chromatin accessibility analysis reveals functional cis-regulatory regions related to fruit development and domestication in tomato.

Non-coding DNA sequences harbor vast regulatory programs that ensure the precise spatiotemporal control of gene expression, which is essential for proper plant development and trait formation. Chromatin accessibility analysis could identify functional DNA regions within the extensive non-coding sequences and infer regulatory elements, serving as a crucial approach to unravel the mysteries of non-coding DNA sequences. Tomato fruit, a fleshy organ, provides a special system for studying fruit development and trait formation. However, the role of cis-accessible chromatin regions (cis-ACRs) during tomato fruit development, particularly in comparison with protein-coding DNA sequences, remains poorly understood. Here, we used ATAC-seq to define the landscape of cis-ACRs during fruit development and domestication in tomato. Temporal differential analysis revealed the dynamic opening and closing of cis-ACRs during fruit development. Comparative analysis of cis-ACRs between cultivated and wild tomatoes highlighted their significant contributions to fruit domestication. Combining analysis with genomic structural variations (SVs) suggested that SVs are likely a key factor in the formation of specific accessible cis-ACRs in cultivated tomatoes. Moreover, using gene editing, we identified a functional cis-ACR within the intron of the MBP3 gene that regulates fruit development and size traits. Overall, our findings provide a comprehensive perspective on the roles of cis-ACRs in tomato fruit development and domestication.

Solanum lycopersicum↗
PubMed2001

Stressor characteristics and post-traumatic stress disorder symptom dimensions in war victims.

AIM: To evaluate how the type of trauma is related to specific symptom patterns in patients with post-traumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria. METHODS: A total of 136 PTSD patients exposed to war-related traumatic experiences were divided in four groups: 79 veterans, 18 former prisoners (who witnessed or were subject to torture or frequent assaults), 15 victims of rape, and 24 refugees from Bosnia and Herzegovina. Each group was homogenous in regard to traumatic experiences. RESULTS: Significant inter-group differences were found in symptoms listed in the DSM-IV criteria, and under criteria C (avoidance) and D (arousal). No such differences were observed in symptoms listed under criterion B (intrusive symptoms). The results indicate that stressor characteristics may play a role not only in the variety of symptoms exhibited, but particularly in the number of avoidance and arousal symptoms. Victims of rape tended to present with more avoidance symptoms and fewer hyperarousal symptoms, whereas former prisoners and veterans tended to report more hyperarousal symptoms. Rape victims and former prisoners also reported more symptoms than the other groups. CONCLUSION: There is a strong indication that stressor characteristics influence the variety and number of exhibited intrusive, avoidance, and arousal symptoms. More research is needed to precisely define individual symptom dimensions possibly relating to particular stressor characteristics. Additional studies are needed to determine whether PTSD, as it is currently defined in the DSM-IV, is really a homogenous diagnostic category.

Adult↗
PubMed2025

A base editor facilitates simultaneous purine and pyrimidine substitutions for ex vivo and in vivo mutagenesis screens.

Genetic mutations are closely linked to human diseases, yet the relationship between many mutations and their corresponding phenotypes remains poorly understood. Furthermore, tools to study the connection between nucleotide variations and phenotypes are limited. To address this issue, we developed ACGBEmax by fusing the dual-functional deaminase, engineered N-methylpurine DNA glycosylase, and evolved SOS response associated peptidase domain with nCas9(D10A). ACGBEmax enables the precise conversion of A, C, and G to other bases in mammalian cells, thereby generating an extensive range of base mutations types. We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed in situ mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.

Animals↗
PubMed2003

Gain in stochastic resonance: precise numerics versus linear response theory beyond the two-mode approximation.

In the context of the phenomenon of stochastic resonance (SR), we study the correlation function, the signal-to-noise ratio (SNR), and the ratio of output over input SNR, i.e., the gain, which is associated to the nonlinear response of a bistable system driven by time-periodic forces and white Gaussian noise. These quantifiers for SR are evaluated using the techniques of linear response theory (LRT) beyond the usually employed two-mode approximation scheme. We analytically demonstrate within such an extended LRT description that the gain can indeed not exceed unity. We implement an efficient algorithm, based on work by Greenside and Helfand (detailed in the Appendix), to integrate the driven Langevin equation over a wide range of parameter values. The predictions of LRT are carefully tested against the results obtained from numerical solutions of the corresponding Langevin equation over a wide range of parameter values. We further present an accurate procedure to evaluate the distinct contributions of the coherent and incoherent parts of the correlation function to the SNR and the gain. As a main result we show for subthreshold driving that both the correlation function and the SNR can deviate substantially from the predictions of LRT and yet the gain can be either larger or smaller than unity. In particular, we find that the gain can exceed unity in the strongly nonlinear regime which is characterized by weak noise and very slow multifrequency subthreshold input signals with a small duty cycle. This latter result is in agreement with recent analog simulation results by Gingl et al. [ICNF 2001, edited by G. Bosman (World Scientific, Singapore, 2002), pp. 545-548; Fluct. Noise Lett. 1, L181 (2001)].

Journal Article↗
PubMed2004

The Child Report Form of the CHIP-Child Edition: reliability and validity.

BACKGROUND: There is increasing recognition of the importance of obtaining children's reports of their health, but significant challenges must be overcome to do so in a systematic, population-based manner. OBJECTIVE: The objective of this study was to present the initial tests of the Child Report Form of the Child Health and Illness Profile-Child Edition (CHIP-CE/CRF), a self-report health status instrument for children 6 to 11 years old. METHODS: Three studies iteratively evaluated revisions of the CHIP-CE/CRF in 4 geographic locations in the United States. Children (N=1708) whose families represent the low to middle socioeconomic strata and predominant U.S. racial/ethnic groups were involved. RESULTS: The final CHIP-CE/CRF includes 5 domains: Satisfaction (with self and health), Comfort (emotional and physical symptoms and limitations), Resilience (positive activities that promote health), Risk Avoidance (risky behaviors that influence future health), and Achievement (of social expectations in school and with peers). The internal consistency and test-retest reliability of the domains are good to excellent, with a definite age gradient such that younger children's responses are less reliable although still acceptable. Validity is supported through criterion and construct validity tests and structural analyses. Standard scores (mean, 50; standard deviation, 10) were established. CONCLUSIONS: Health status can be reliably and validly assessed directly from children 6 to 11 years old on the CHIP-CE/CRF. In combination with the CHIP-AE, self-reported health status can now be obtained from youth 6 to 18 years old using a consistent conceptual framework. This can greatly improve the precision and comparability of health assessments of youth, enhancing the validity of outcome research and longitudinal studies across childhood and adolescence.

Adaptation, Psychological↗
PubMed2001

New approaches to lymphoma diagnosis.

Recent years have brought an explosion of new diagnostic tools to the pathology of lymphomas, which have permitted more precise disease definition and recognition of factors that can predict prognosis and response to treatment. These new methods exploit both the biological features of normal lymphocytes as they progress through differentiation pathways and the genetic abnormalities that characterize malignant transformation. These features can be assessed in individual tumors with techniques that detect proteins (immunophenotyping), messenger RNA (in-situ hybridization), or changes in DNA [Southern blot, PCR, fluorescence in-situ hybridization (FISH), and gene sequencing]. Recently, the novel technology of "gene chips" or DNA microarrays has greatly enhanced the efficiency of analyzing expression of many genes simultaneously at the RNA level. Understanding the relationship of lymphoid neoplasms to their normal counterparts and the genetic events that lead to malignant transformation in lymphoid cells are essential for physicians caring for patients with lymphoma, since these are the basis of modern classification, diagnosis, and prognosis prediction. Although microarray technology is not ready for prime time in the daily diagnosis of lymphoma, practitioners should understand its potential and limitations. The vast majority of lymphoid neoplasms worldwide are derived from B lymphocytes at various stages of differentiation. The review by Harald Stein and colleagues present the events of normal B-cell differentiation that are relevant to understanding the biology of B-cell neoplasia. These include antigen receptor [immunoglobulin (Ig)] gene rearrangement, somatic mutations of the Ig variable region genes, receptor editing, Ig heavy chain class switch, and differential expression of a variety of adhesion molecules and receptor proteins as the cell progresses from a precursor B cell to a mature plasma cell. Most lymphoid neoplasms have genetic abnormalities, many of which appear to occur during the gene rearrangements and mutations that characterize normal B-cell differentiation. Dr. Riccardo Dalla Favera reviews the mechanisms of these translocations and other abnormalities, and their consequences for lymphocyte biology. The association of specific abnormalities with individual lymphomas is reviewed. Dr. Wing C. Chan reviews the technology and applications of DNA microarray analysis, its promises and pitfalls, and what it has already told us about the biology of lymphomas. Finally, what does this all mean? The applications, both current and future, of these discoveries to the diagnosis and treatment of patients with lymphoma are discussed by Dr. Nancy Lee Harris.

Cell Differentiation↗
PubMed2026

Advances in the diagnosis and classification of B-ALL: comparative insights from updated guidelines.

Accurate molecular classification is essential for diagnosis, risk stratification, and treatment selection in B-cell lymphoblastic leukemia (B-ALL). In this study, we performed a comprehensive, real-world reclassification of 1015 consecutively diagnosed B-ALL patients using the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the International Consensus Classification (ICC). An integrative genomic strategy that combined whole transcriptome sequencing, fusion detection, mutational analysis, and cytogenetics enabled reclassification according to both the WHO-HAEM5 and ICC frameworks, thereby substantially reducing the proportion of unclassifiable B-ALL from 41.9% (2016 WHO revision [WHO-HAEM4R]) to 15.9% (WHO-HAEM5) and 11.9% (ICC). Distinct clinical and prognostic features were identified across newly defined subtypes. Multivariable analysis confirmed that this genomic classification is a robust, independent predictor of survival after adjusting for age, minimal residual disease status, and transplant intervention. Specifically, HLF-rearranged and MEF2D-rearranged B-ALL conferred a persistently poor prognosis across all age groups despite allogeneic hematopoietic stem cell transplantation, highlighting an urgent need for novel therapeutic strategies. Gene expression profiling resolved cryptic subtypes, including ETV6::RUNX1-like, ZNF384-rearranged-like, and BCR::ABL1-like B-ALL, and uncovered diagnostic ambiguity in patients with concurrent lesions. In addition, we report emerging high-risk groups, including IDH1/2- and ZEB2 Q1072-mutated B-ALL, that may warrant recognition as distinct molecular entities. Our findings demonstrate the clinical use of integrative transcriptomic profiling in refining B-ALL taxonomy in guiding risk-adapted therapies and informing future revisions of diagnostic standards. This study supports the incorporation of high-throughput molecular diagnostics into routine leukemia classification and precision treatment planning.

Humans↗
PubMed2002

[Experience in treating acromegalic patients with long-acting octreotide].

The authors report clinical observations in 12 acromegalic patients treated with long-acting octreotide (Sandostatin LAR, Novartis, 20 mg intramuscular injection per 28 days administered for 6-36 months). Clinically and hormonally active acromegaly was evidenced in all patients by the presence of typical clinical symptoms, increased serum growth hormone and insulin-like growth factor I concentrations, and by non-suppressible serum growth hormone levels after oral glucose administration. In all patients previous treatments (transsphenoidal surgery, pituitary irradiation and bromocriptine therapy) were uneffective or contraindicated, or they were refused by the patients. Octreotide test (Sandostatin, Novartis, 100 g subcutaneously) performed in all patients before treatment precisely predicted the hormonal effectiveness of long-acting octreotide treatment. Three-six months after therapy serum growth hormone levels decreased from 13.6 +/- 3.9 ng/ml (mean +/- SD) to 3.4 +/- 1.7 ng/ml, while insulin-like growth factor I concentrations decreased from 483 +/- 127 ng/ml to 248 +/- ng/ml. Of the 12 patients 7 (58%) had serum growth hormone levels considered as safe values (< 2.5 ng/ml), whereas in 9 patients (75%) serum insulin-like growth factor I concentrations returned to age- and sex-matched normals. Repeat pituitary magnetic resonance imaging performed in 8 patients treated longer than 1 year revealed a decrease of tumor size in 3 patients (37%). There was a considerable clinical improvement during treatment: severe headache, which was present in most patients, as well as perspiration, joint pain, swelling of extremities, and weakness markedly decreased or disappeared. These results indicate that long-acting octreotide offers a very effective treatment of choice in acromegalic patients in whom other previous therapies were ineffective, contraindicated, or refused.

Acromegaly↗
PubMed2025

Targeted loss of heterozygosity in Candida albicans using CRISPR-Cas9 reveals the functional impact of allelic variation.

The diploid genome of the fungal pathogen Candida albicans is highly heterozygous, with most allele pairs diverging at either the coding or regulatory level. When faced with selection pressure like antifungal exposure, this hidden genetic diversity can provide a reservoir of adaptive mutations through loss of heterozygosity (LOH) events. Validating the potential phenotypic impact of LOH events observed in clinical or experimentally evolved strains can be difficult due to the challenge of precisely targeting one allele over the other. Here, we show that a CRISPR-Cas9 system can be used to overcome this challenge. By designing allele-specific guide RNA sequences, we can induce targeted, directed LOH events, which we validate by whole-genome long-read sequencing. Using this approach, we efficiently recapitulate a recently described LOH event that increases resistance to the antifungal fluconazole. Additionally, we find that the recombination tracts of these induced LOH events have similar lengths to those observed naturally. To facilitate future use of this method, we provide a database of allele-specific sgRNA sequences for Cas9 that provide near genome-wide coverage of heterozygous sites through either direct or indirect targeting. This approach will be useful in probing the adaptive role of LOH events in this important human pathogen.

Candida albicans↗
PubMed2003

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation.

In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch mu DNA region, CSR, and the SHM in 65 CLL patients. Our results demonstrate that unmutated CLL B cells can constitutively express AID and that AID expression is associated with the presence of mutations in the preswitch region and in clonally related isotype-switched transcripts. They also demonstrate that in CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process. Our results show a dissociation between SHM and CSR in CLL and suggest that, in this disease, AID would require additional help for carrying out the SHM process.

B-Lymphocytes↗