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Biomedical subjects

F Young

Publications and source records attributed to F Young.

At least 37 records · Page 2Linked to original sources
PubMed1994

Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.

To study the influence of immunoglobulin heavy-chain (HC) and light-chain (LC) expression in promoting B-cell differentiation, we have introduced functional immunoglobulin HC and/or LC transgenes into the recombinase activating gene-2-deficient background (RAG-2-/-). RAG-2-/- mice do not undergo endogenous V(D)J rearrangement events and, therefore, are blocked in B- and T-cell development at the early pro-B- and pro-T-cell stages. Introduction of immunoglobulin HC transgenes into the RAG-2-/- background promotes the development of a B-lineage cell population that phenotypically has the characteristics of pre-B cells. We have shown further that this population has altered growth characteristics as measured by interleukin-7 responsiveness in culture. Bone marrow cells from immunoglobulin HC transgenic RAG-2-/- mice have up-regulated expression of germ-line kappa LC gene transcripts and down-regulated expression of lambda 5 surrogate LCs (SLCs). Although mu HC/SLC complexes are detectable intracellularly in HC/RAG-2-/- pre-B-cell populations, HC expression is not readily detectable on the surface of these cells. lambda LC RAG-2-/- mice had a bone marrow B-lineage cell phenotype indistinguishable from that of RAG-2-/- littermates, indicating that LC expression by itself has no influence on pro-B cell differentiation. Strikingly, simultaneous introduction of mu HC and lambda LC transgenes into RAG-2-/- mice led to the generation of a substantial population of "monoclonal" peripheral B-cells that were functional with regard to immunoglobulin secretion, indicating that T cells or diverse immunoglobulin repertoires are not necessary for peripheral B-cell development.

Animals↗
PubMed1994

The expression of Vpre-B/lambda 5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice.

Precursor B (pre-B) cells in bone marrow of normal and B cell-deficient mutant mice were analyzed for the expression of Vpre-B/lambda 5 surrogate light chain (SL). The surface expression of SL is confined to the early stages (pro-B and pre-B-I) of pre-B cell development and becomes undetectable once mu heavy chain (microH) is produced. The cell-cycle analysis revealed that cytoplasmic microH+ large cells (large pre-B-II), approximately 30% of which coexpressed SL in the cytoplasm, were most actively cycling, whereas cytoplasmic microH+ small cells (small pre-B-II) were SL- and not in cycle. The analysis of pre-B cells in B cell-deficient mice suggests that the large pre-B-II stage is a critical step for the selection and amplification of cells carrying functionally rearranged microH genes.

Animals↗
PubMed1994

Probing immune functions in RAG-deficient mice.

Inactivation of recombination activating gene (RAG)-1 or RAG-2 in mice results in the inability of developing lymphocytes to initiate V(D)J recombination, leading to the arrest of lymphocyte differentiation at a very early stage. Introduction of functionally assembled antigen-receptor genes or other potentially relevant genes into the RAG-deficient background can bypass the V(D)J recombination block and promote differentiation of the lymphocytes of RAG-deficient mice to various stages. This approach offers new means for analyzing the control of lymphocyte differentiation. In addition, generation of somatic chimeric mice by injecting mutant embryonic stem cells into the RAG-2-deficient blastocysts has also provided a powerful new method for assaying the potential roles of genes or regulatory elements in lymphocyte development or function.

Animals↗
PubMed1994

IL-2 receptor alpha chain expression during early B lymphocyte differentiation.

The IL-2/IL-2 receptor (IL-2R) has been studied intensively because of its potential function in the development and regulation of the immune system. The IL-2R alpha chain has been shown to be expressed on CD4-CD8- thymocytes and activated T and B cells. In this report, we show that IL-2R alpha is also expressed on precursor B cells in the bone marrow. Its expression is initiated by functional rearrangement and expression of Ig mu heavy chain gene and is down-regulated when immature B cells mature and express IgD. Its potential function in early B cell differentiation is discussed in comparison with its role in thymocyte differentiation.

Animals↗
PubMed1993

RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development.

We describe a system to evaluate the function of lymphocyte-specific and generally expressed genes in the differentiation and/or function of lymphocytes. RAG-2 (recombination-activating gene 2)-deficient mice have no mature B and T lymphocytes due to the inability to initiate VDJ recombination. Blastocysts from RAG-2-deficient mice generate animals with no mature B and T cells following implantation into foster mothers. However, injection of normal ES cells into RAG-2-deficient blastocysts leads to the generation of somatic chimeras with mature B and T cells all of which derive from the injected ES cells (referred to as RAG-2-deficient blastocyst complementation). Complementation of RAG-2-deficient blastocysts with mutant ES cells heterozygous for a targeted mutation that deletes all immunoglobulin heavy-chain joining (JH) gene segments (JH+/-) also leads to generation of chimeras with normal B and T cells. However, complementation with ES cells homozygous for the JH mutation (JH-/-) generates animals with normal T cells but no B cells, due to a block in B-cell development at a very early stage. Transfection of a functionally assembled mu heavy-chain gene into the JH-/- ES cells prior to blastocyst injection rescues the JH-/- mutation and allows the generation of both mature T and mature B cells. The rescued B cells express IgM but not IgD and respond normally to bacterial lipopolysaccharide stimulation by proliferating and by secreting IgM.

Animals↗
PubMed1993

B cell development in mice that lack one or both immunoglobulin kappa light chain genes.

We have generated mice that lack the ability to produce immunoglobulin (Ig) kappa light chains by targeted deletion of J kappa and C kappa gene segments and the intervening sequences in mouse embryonic stem cells. In wild type mice, approximately 95% of B cells express kappa light chains and only approximately 5% express lambda light chains. Mice heterozygous for the J kappa C kappa deletion have approximately 2-fold more lambda+ B cells than wild-type littermates. Compared with normal mice, homozygous mutants for the J kappa C kappa deletion have about half the number of B cells in both the newly generated and the peripheral B cell compartments, and all of these B cells express lambda light chains in their Ig. Therefore, homozygous mutant mice appear to produce lambda-expressing cells at nearly 10 times the rate observed in normal mice. These findings demonstrate that kappa gene assembly and/or expression is not a prerequisite for lambda gene assembly and expression. Furthermore, there is no detectable rearrangement of 3' kappa RS sequences in lambda+ B cells of the homozygous mutant mice, thus rearrangements of these sequences, per se, is not required for lambda light chain gene assembly. We discuss these findings in the context of their implications for the control of Ig light chain gene rearrangement and potential applications of the mutant animals.

Animals↗
PubMed1993

Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus.

To investigate the role of intronic immunoglobulin heavy chain (IgH) enhancer (E mu) in generating accessibility of the JH locus for VDJ recombination, we generated ES cells in which E mu or its flanking sequences were mutated by replacement with or insertion of an expressed neor gene. Heterozygous mutant ES cells were used to generate chimeric mice from which pre-B cell lines were derived by transformation of bone marrow cells with Abelson murine leukemia virus (A-MuLV). Comparison of the rearrangement status of the normal and mutated alleles in individual pre-B cell lines allowed us to assay for cis-acting effects of the mutations. Replacement of a 700 bp region immediately downstream from the core E mu [which includes part of the 3' matrix associated region (MAR) and the I mu exon] had no obvious effect on rearrangement of the targeted allele, indicating that insertion of a transcribed neor gene into the JH-C mu intron does not affect JH accessibility. In contrast, replacement of an overlapping 1 kb DNA fragment that contains the E mu resulted in a dramatic cis-acting inhibition of rearrangement, demethylation and germline transcription of the associated JH locus. Surprisingly, insertion of the neor gene into the 5' MAR sequence approximately 100 bp upstream of the core E mu also dramatically decreased recombination of the linked JH locus; but, in many lines, did not prevent demethylation of this locus. We conclude that integrity of the E mu and upstream flanking sequences is required for efficient rearrangement of the JH locus and that demethylation of this locus, per se, does not necessarily make it a good substrate for VDJ recombination.

Animals↗
PubMed1993

Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus.

B lymphocyte differentiation is characterized by an ordered series of Ig gene assembly and expression events. In the majority of normal B cells, assembly and expression of Ig heavy (H) chain genes precedes that of light (L) chain genes. To determine the role of the Ig heavy chain protein in B cell development and L chain gene rearrangement, we have generated mice that cannot assemble Ig H chain genes as a result of targeted deletion of the JH gene segments in embryonic stem cells. Mice homozygous for this deletion are devoid of slg+ B cells in the bone marrow and periphery. B cell differentiation in these mice is blocked at the large, CD43+ precursor stage. However, these precursor B cells do assemble kappa L chain genes at a low level in the absence of mu H chain proteins. These data demonstrate that rearrangement and expression of the mu H chain gene is not absolutely required for kappa L chain gene rearrangement in vivo. Expression of mu chains may facilitate either efficient L chain gene rearrangement or the survival of cells that have rearranged light chain genes by promoting the differentiation of large, CD43+ to small, CD43- pre-B cells.

Animals↗
PubMed1993

Perceptual dimensions of tactile surface texture: a multidimensional scaling analysis.

The purpose of this study was to examine the subjective dimensionality of tactile surface texture perception. Seventeen tactile stimuli, such as wood, sandpaper, and velvet, were moved across the index finger of the subject, who sorted them into categories on the basis of perceived similarity. Multidimensional scaling (MDS) techniques were then used to position the stimuli in a perceptual space on the basis of combined data of 20 subjects. A three-dimensional space was judged to give a satisfactory representation of the data. Subjects' ratings of each stimulus on five scales representing putative dimensions of perceived surface texture were then fitted by regression analysis into the MDS space. Roughness-smoothness and hardness-softness were found to be robust and orthogonal dimensions; the third dimension did not correspond closely with any of the rating scales used, but post hoc inspection of the data suggested that it may reflect the compressional elasticity ("springiness") of the surface.

Adolescent↗
PubMed1992

RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.

We have generated mice that carry a germline mutation in which a large portion of the RAG-2 coding region is deleted. Homozygous mutants are viable but fail to produce mature B or T lymphocytes. Very immature lymphoid cells were present in primary lymphoid organs of mutant animals as defined by surface marker analyses and Abelson murine leukemia virus (A-MuLV) transformation assays. However, these cells did not rearrange their immunoglobulin or T cell receptor loci. Lack of V(D)J recombination activity in mutant pre-B cell lines could be restored by introduction of a functional RAG-2 expression vector. Therefore, loss of RAG-2 function in vivo results in total inability to initiate V(D)J rearrangement, leading to a novel severe combined immune deficient (SCID) phenotype. Because the SCID phenotype was the only obvious abnormality detected in RAG-2 mutant mice, RAG-2 function and V(D)J recombinase activity, per se, are not required for development of cells other than lymphocytes.

Animals↗
PubMed1992

VDJ recombination.

The ability of lymphocyte receptor V, D and J gene segments to rearrange generates much of the receptor diversity that is the hallmark of the immune system. Naturally, the mechanisms of immunoglobulin and T-cell receptor gene recombination are of enormous interest. Here, Fred Alt and colleagues review current understanding of the process and speculate on future findings.

Animals↗
PubMed1991

Empowering middle managers in hospitals with team-based problem solving.

A team-oriented problem-solving procedure using management project teams was developed to improve quality of care and productivity in a private, nonprofit hospital. A focus group of managers developed the procedure, endorsed by top management. The work of four manager teams that followed the procedure saved the hospital more than $500,000.

Decision Making, Organizational↗
PubMed1990

Molecular analysis of a germ line-encoded idiotypic marker of pathogenic human lupus autoantibodies.

Id-16/6 is an idiotypic marker found in both IgM and IgG antibodies, as well as in the tissue lesions of patients with SLE. The prototypic Id-16/6+ mAb is 18/2, whose VH3-derived H chain is encoded by an unmutated germ-line gene. We found that the H chains of VH3-derived Id-16/6+ antibodies contain the major determinants of Id-16/6. Moreover, B cell clones from which those antibodies were harvested produce RNA that hybridized under conditions of high stringency to oligonucleotide probes corresponding to the CDR of the VH segment of 18/2. Western blots of Id-16/6+ mAbs with anti-Id confirmed the association of the Id with H chains. Id-16/6 can identify a subgroup of VH3-derived antibodies we have termed the 18/2 CDR family. However, Id-16/6 can also be expressed in some antibodies unrelated to the 18/2 CDR family. No characteristic Ag-binding specificity was found among the members of the 18/2 CDR family. The principal phenotypic feature shared by all known members of the family is Id-16/6.

Amino Acid Sequence↗
PubMed1990

Individual VH genes detected with oligonucleotide probes from the complementarity-determining regions.

The germ-line and expressed Ig repertoire was examined with three oligonucleotide probes from the CDR regions of VH18/2, a VH gene from the largest human VH gene family, VHIII. Each oligonucleotide probe detected small numbers of germ-line bands (1-5) under conditions in which single base differences can be detected; more than half of these bands were polymorphic. The combined results from pairs of oligonucleotides from CDR1 and CDR2 identified a single band on Southern blots, as did a probe from the 5' end of CDR2. This band contains the 18/2 germ-line gene. The nucleotide sequence of expressed VH genes that hybridized to both CDR probes or to the 5' CDR2 probe were greater than or equal to 97% homologous to 18/2 in both the framework and CDR regions. This group of closely related VH genes, the 18/2 CDR family, appears to be overexpressed. The role of polymorphisms and differential expression of individual V genes in multigenic autoimmune diseases, as well as the organization and expression of individual V genes, can be examined with pairs of oligonucleotides from CDR1 and the 3' end of CDR2, or with probes from the 5' end of CDR2.

Amino Acid Sequence↗
PubMed1989

Healing, regeneration, and repair: prospectus for new dental treatment.

Recent advances in our understanding of growth and development have led us to the realization that previously unattainable tissue regeneration and repair are now within the scope of patient care. Concurrent and complementary use of nonbiological substitutes, with complete biological integration and host acceptance, is becoming a leading recognized alternative to the loss of function of biological tissues. This manuscript will examine the implications of the new biotechnology in medical sciences for dental healing, regeneration, and repair. These concepts, when coupled with genetic engineering, could produce enormous changes in the quality of life.

Humans↗
PubMed1987

Body weight, blood pressure, and electrolyte excretion of young adults from six ethnic groups in Hawaii.

There is positive correlation between high dietary intake of sodium and prevalence of hypertensive disease. Dietary potassium shows a negative correlation with this prevalence. Racial background of subjects may affect such relationships. This is a study of the relationships between ethnicity and blood pressure in young adults of six ethnic groups in Hawaii. Body weight, electrolyte excretion, which may reflect intake, and blood pressure of the subjects are reported here. Caucasians and Hawaiians and part-Hawaiian young adults tended to be taller and heavier than the Chinese, Filipinos, Japanese, and Koreans. Both systolic and diastolic pressures were significantly higher in males than in females (all races combined). No significant differences between sexes or races were found in urinary excretion of sodium and potassium or in urinary sodium:potassium ratios. Body weight and Quetelet's Index but not sodium:potassium ratio correlated significantly with diastolic pressure.

Adult↗
PubMed1979

Simple and choice reaction time methods in the study of motor programming.

In an extensive series of experiments Sternberg, Monsell, Knoll, and Wright (1978) reported that simple RT increased as a linear function of the number of items to be pronounced or typed. The present experiments replicate a portion of these results, but show that the effect is less general than may have been supposed. Since the effect does not occur in every case in which a response programming interpretation would predict it, this interpretation must be rejected. This conclusion is consistent with the viewpoint that response programming should be investigated in a choice- rather than simple-RT paradigm. In this view, motivated subjects can program responses in advance of the simple-RT interval because the particular response to be made has been precued. Effects of response parameters which are observed for motivated subjects in the simple-RT paradigm, such as those reported by Sternberg et al. (1978), should be attributed to processes other than programming motor responses.

Journal Article↗