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PubMed2003

DNA variability of human genes.

We have investigated the level of DNA-based variation (both SNPs and haplotypes) for several thousand human genes. In addition, we have characterized how this variation is distributed in a number of biologically and clinically important ways. First, we have determined how SNPs are distributed within human genes: where they occur relative to various functional regions; levels of variability of human SNPs; pattern of the molecular sequence of SNPs; and how these compare with the corresponding sequence of a chimpanzee. Second, we have determined how these aspects of SNP distribution vary among four human population samples. All genes were sequenced on DNA obtained from 82 unrelated individuals: 20 African-Americans, 20 East Asians, 21 European-Americans, 18 Hispanic-Latinos and three Native Americans. In particular, we looked at patterns of SNP and haplotype sharing among the four larger population samples. Third, we have determined the patterns of linkage disequilibrium among SNPs, which also determines the haplotype variability of each gene. These characteristics also vary substantially among populations. A deeper understanding of these aspects of human genetic variation will be of vital importance when trying to identify the genetic contribution to complex phenotypes such as aging.

Aging↗

PubMed1983

An assessment of cerebral dominance in language--disordered children via a time-sharing paradigm.

A time-sharing paradigm was used to assess language lateralization in language-disordered and normal children aged 4-7 years. Several expressive language tasks as well as a vocal, but nonlinguistic, task were administered concurrently with unimanual finger tapping. Dependent variables were percent disruption scores and number of syllables produced per concurrent trial. All language concurrent tasks produced tapping reductions for both hands for both groups. This result contrasts to similar time-sharing studies claiming asymmetrical interference and hence language lateralization in children (N. White & M. Kinsbourne, 1980, Brain and Language 10, 215-223; J. Obrzut, G. Hynd, A. Obrzut, & J. Leitgeb, 1980, Brain and Language 11, 181-194). A multiple regression analysis revealed a significant interaction effect differentiating language-disordered from normal children. Normals exhibited a parallel response pattern for speech and tapping (both increased or decreased in rate) under all lateralization conditions. Language-disordered children exhibited an inverse response pattern (e.g., if speech output increased, tapping rate decreased) only under left-hemisphere time-sharing.

Child↗

PubMed1994

Mapping the upstream boundary of somatic mutations in rearranged immunoglobulin transgenes and endogenous genes.

Mammalian B-cell specific somatic hypermutation contributes to affinity maturation of the antibody response. This mutator activity is highly focused on rearranged immunoglobulin variable regions, but the underlying mechanism remains to be elucidated. In an effort to gain insights into the mechanism of somatic hypermutation, the precise distribution and frequency of mutations upstream of murine immunoglobulin genes was determined by examining the same variable gene segments when mutated in different B-cell lines. Immunoglobulin sequences analysed included kappa light chain transgenes bearing mutated V kappa 24 variable regions, and the endogenous V kappa gene isolated from myeloma MOPC167, which also exhibits mutations in the variable region. In addition, mutated endogenous VH1 gene segments of the S107 heavy chain variable gene family were also examined. For both VH1 and V kappa 24, somatic mutations were generally not found upstream of the leader intron, even in genes which exhibited a high mutation frequency in the variable region itself. The 5' somatic mutation boundary identified in immunoglobulin transgenes overlaps the boundary observed in endogenous genes, suggesting that both share cis-elements required for defining the mutable domain. Furthermore, the location of this 5' boundary appears not to change when these immunoglobulin genes are examined in different cell lines. These data may be indicative of a defined start site for immunoglobulin mutator activity.

Animals↗

PubMed2025

Tonic signaling of the B-cell antigen-specific receptor is a common functional hallmark in chronic lymphocytic leukemia cell phosphoproteomes at early disease stages.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B-CLL and CLL-like monoclonal B-cell lymphocytosis (MBL) primary cells. Using high-resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange-PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B-CLL and MBL phosphoproteomes, notably tonic signaling (low-level, constitutive signaling) of the B-cell antigen-specific receptor (BCR) and nuclear factor NF-kappa-B (NF-kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B-CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.

Humans↗

PubMed1988

Lifestyle factors in monozygotic and dizygotic twins.

In examining genetic influences on biological variables using twins, it may be important to examine the distribution between and within twin pairs of demographic and lifestyle factors that may themselves affect the biological variable being studied. We explored the distribution of demographic and lifestyle factors that may affect blood lipid levels or ischaemic heart disease (IHD) risk among a sample of 106 monozygotic (MZ) and 94 like-sex dizygotic (DZ) twin pairs. In our sample, MZ twins were statistically significantly different from DZ twins only in marital status, cigarette smoking habits, and the ratio of polyunsaturated to saturated fat (P:S ratio) in their dietary intake. The latter variable was among many dietary variables examined (using 4-day weighed food diaries), and the size of the difference in intake was small. When comparisons were made of the similarities within twin pairs, we found members of MZ twin pairs to be statistically significantly closer than DZ twins in educational achievement, occupation, cigarette smoking, and exercise habits, and the number of days a week on which alcohol was consumed. These last three variables were consistently closer among twins with closer contact than among those with a smaller degree of current shared environment. For 12 of the 13 nutrients examined, the within-pair correlations were higher for MZ than for DZ twins, although our test for significant genetic variance showed statistical significance only for intake of complex carbohydrates. We conclude that MZ twins share demographic and lifestyle factors that might influence the risk of IHD and blood lipid levels to a greater degree than do DZ twins, although it is difficult to say if these similarities in lifestyle result from genetic influences or not. Nevertheless, ascribing differences between correlations in MZ and DZ twin pairs for lipid levels as being purely "genetic"--as implicit in conventional measures of heritability--is likely to overestimate the influence of genetic factors.

Adolescent↗

PubMed1997

Liver transplantation in Asian patients with chronic hepatitis B.

It has been suggested that Asian patients have reduced survival after liver transplantation because of greater recurrence of hepatitis B virus (HBV). We analyzed the outcome of Asian and non-Asian patients receiving transplants for chronic hepatitis B between May 1988 and March 1994. Baseline Child-Pugh score and United Network for Organ Sharing (UNOS) status, HBV recurrence, and survival were compared between the two groups. All but one patient received variable doses of hepatitis B immune globulin. Mean follow-up of surviving patients was 28 months (range, 3-71 months). Fifteen Asians and 20 non-Asians underwent transplantation. Six of 15 Asians (40%) and 4 of 20 non-Asians (20%) died during the study period. Although Asians had a lower 1-year survival than non-Asians (59% for Asians and 94% for non-Asians), the 5-year actuarial survival was not different (59% and 57% for Asians and non-Asians, respectively). The causes of death in 5 of 6 Asians were factors other than recurrent hepatitis B, and 4 of 5 deaths occurred within 60 days after transplantation. Eighty percent of Asian patients were Child-Pugh class C at referral, compared with 50% of non-Asians, and Asians were more likely to be status 1 at transplantation (40% vs. 10%; P < .05). By contrast, all four deaths in non-Asians occurred late and were secondary to recurrent HBV infection. Of patients surviving more than 60 days after transplantation, 7 of 11 Asians (64%) and 10 of 20 non-Asians (50%) developed recurrent HBV infection (NS). Late mortality attributable to HBV recurrence was lower but not significantly different in Asians (1 of 7 [14%]) than in non-Asians (4 of 10 [40%]). In summary, HBV recurrence and late HBV-related mortality in Asians and non-Asians is similar after liver transplantation for chronic hepatitis B. Late referral and more advanced chronic liver disease at the time of transplantation probably account for the lower 1-year survival of Asians after liver transplantation.

Chronic Disease↗

PubMedDate not supplied

Clavicles, scapulae and humeri from the Sima de los Huesos site (Sierra de Atapuerca, Spain).

The scapulae, clavicles and humeri recovered from the Sima de los Huesos (SH) site between 1976 and 1994 are studied. All elements are briefly described anatomically with metrics and compared with other fossil hominids in order to establish the morphological pattern of the SH hominids. A minimum of 13 individuals are represented by the humeri in the SH sample. Almost all of them can be classified as adolescents and young adults. The morphology of the SH hominid shoulder girdle and humeri indicates that much of the shoulder morphology recognized in the later true Neandertal was present in Europe long before they appeared. Thus, this morphological pattern is not exclusive to Neandertals alone. The SH clavicles, scapulae and humeri share with the Neandertals many traits usually considered to be Neandertal specializations. The comparative analysis of the SH evidence suggests that most of the SH and Neandertal shared traits are either primitive features within the genus Homo or even for all hominids, or display high variability within different hominid samples. These traits must be used with caution, or not used at all, in phylogenetic analysis. There are, however, traits that to date have only been detected in the SH hominids and the Neanderials, which could be exclusive to the European phyletic lineage (clade) of Homo.

Adolescent↗

PubMed1980

Antigen specific T cell factors.

Antigen specific helper and suppressor factors have a similar structure, with two major sections, a 'variable region', determining antigen specificity which is likely to be controlled by Immunoglobulin VH genes, with which it shares idiotype and framework determinants. Specific factors also have a 'constant region' which does not vary between strains and minimally between species or with the antigenic specificity of the factors, which are defined by rabbit anti-helper or anti-suppressor antisera. This region determines the biological function of the molecule. Anti-Ia antisera react with factors, but the nature and function of Ia molecules on T cell factors is still unclear. The model of specific factor structure, with C and V regions resembles that of immunoglobulin, and it is thus possible that the C region of factors, like the V region is Ig linked. Because there are multiple T cells, helping and suppressing antibody responses specifically, it seems improbable that all of these cells could interact directly with rare antigen-specific B cells. Thus we propose that macrophage presenting cells are the key to the integration of signals for immune induction and regulation for T and B cells. Since Ir genes have been identified in the macrophage presenting cells interacting with both T and B cells, this suggests that macrophage Ia antigens are of importance in the integration of triggering signals for the lymphoid pool.

Animals↗

PubMed1982

Characterization of a new human cell line derived from a xenografted embryonal carcinoma.

A human cell line has been established from a transplantable xenografted human testicular tumor, which, both in the original tumor and in the xenograft, exhibited the histological characteristics of an undifferentiated malignant teratoma (embryonal cell carcinoma). The cells in culture were undifferentiated by biochemical, morphological, and ultrastructural criteria, growing as small islands of cells that tended to form aggregates at high density. The cells showed some variation in chromosome number with 30 to 40% of the cells having a normal human karyotype. The cells expressed high levels of alkaline phosphatase, which by heat inactivation and inhibition studies was 40 to 50% placental type alkaline phosphatase. None of the cultures produced human chorionic gonadotrophin, alphafetoprotein, carcinoembryonic antigen, or fibronectin, although at high cell densities plasminogen activator could be detected at low levels. Cell surface studies showed that the cells shared antigens with the murine embryonal carcinoma cell line F9, expressed beta 2-microglobulin at very low and variable levels, and bound the lectin peanut agglutinin. These studies suggest that this cell line has some of the characteristics described for murine embryonal carcinoma cell lines.

Alkaline Phosphatase↗

PubMed2002

Neuronal co-localization of different isoforms of tachykinin-related peptides (LemTRPs) in the cockroach brain.

Seven isoforms of tachykinin-related peptides (TRPs) have been isolated from the brain of the cockroach Leucophaea maderae. These peptides (LemTRP-1, 2, and 5-9) share the C-terminal sequence GFX(1)GX(2)Ramide (where X(1) and X(2) are variable residues). In order to determine the neuronal distribution of several of these LemTRP isoforms, we raised antisera to their variable N-termini. Antisera to LemTRP-1, 2, 3, 7, and 8 were utilized for immunocytochemistry on cryostat sections of the L. maderae brain. As expected, the gut peptide LemTRP-3 was not detected in the brain, and the antisera to LemTRP-1, 2, and 7 labeled the same sets of neurons in different regions of the brain. These neurons could also be labeled with antisera raised to the more conserved C-termini of LemTRP-1 and the locust TRP LomTK-I. The antiserum to LemTRP-8 predominantly labeled a set of neurons distinct from that seen with any other N- or C-terminus-directed antisera, suggesting that it recognizes epitope(s) other than known insect TRPs. Our findings indicate that at least three of the LemTRPs are always co-localized in neurons of the L. maderae brain. We have also been able to show that LemTRP-2, which is an N-terminally extended form (17-mere) of LemTRP-1 with a dibasic putative cleavage site, is transported throughout the processes of the neurons in the same manner as LemTRP-1 and 7. Thus, LemTRP-2 may be released with the other shorter LemTRPs. This is the first investigation of LemTRP distribution in the cockroach central nervous system utilizing antisera to native peptides.

Amino Acid Sequence↗

PubMed2006

Development of an alarm sound database and simulator.

OBJECTIVES: The purpose of this study was to develop an interactive software package of alarm sounds to present, recognize and share problems about alarm sounds among medical staff and medical manufactures. METHODS: The alarm sounds were recorded in variable alarm conditions in a WAV file. The alarm conditions were arbitrarily induced by modifying attachments of various medical devices. The software package that integrated an alarm sound database and simulator was used to assess the ability to identify the monitor that sounded the alarm for the medical staff. RESULTS: Eighty alarm sound files (40MB in total) were recorded from 41 medical devices made by 28 companies. There were three pairs of similar alarm sounds that could not easily be distinguished, two alarm sounds which had a different priority, either low or high. The alarm sound database was created in an Excel file (ASDB.xls 170 kB, 40 MB with photos), and included a list of file names that were hyperlinked to alarm sound files. An alarm sound simulator (AlmSS) was constructed with two modules for simultaneously playing alarm sound files and for designing new alarm sounds. The AlmSS was used in the assessing procedure to determine whether 19 clinical engineers could identify 13 alarm sounds only by their distinctive sounds. They were asked to choose from a list of devices and to rate the priority of each alarm. The overall correct identification rate of the alarm sounds was 48%, and six characteristic alarm sounds were correctly recognized by beetween 63% to 100% of the subjects. The overall recognition rate of the alarm sound priority was only 27%. CONCLUSIONS: We have developed an interactive software package of alarm sounds by integrating the database and the alarm sound simulator (URL: http://info.ahs.kitasato-u.ac.jp/tkweb/alarm/asdb.html ). The AlmSS was useful for replaying multiple alarm sounds simultaneously and designing new alarm sounds interactively.

Biomedical Engineering↗

PubMed1975

Defective epithelial adhesion in anterior corneal dystrophies.

Experimental and pathologic studies implicated the role of the epithelial basement membrane and its associated hemidesmosomes and anchoring fibrils in mediating tight adhesion between corneal epithelium and stroma. We evaluated the ultrastructural quality of basement membrane complexes in patients with Reis-Bücklers dystrophy, Cogan's microcystic dystrophy, and nontraumatic recurrent erosion who presented with clinically significant erosive symptoms. Despite the variable clinical and histopathologic appearances among these dystrophies, incompleteness of basement membrane complexes apparently was a common fault shared by these erosive disorders. Such basic incompetence at the basement membrane level can both provoke and sustain erosions, while the more individual pathologic manifestations of a given anterior dystrophy may be of less primary significance.

Adolescent↗

PubMed1996

Burn repetitions in Ghanaian children: prevalence, epidemiological characteristics and socioenvironmental factors.

This paper reports the prevalence, epidemiological characteristics and socioenvironmental-factors for burn repetitions in Ghanaian children newborn to 5 years old using a population-based survey. Mothers of children identified in a survey with burn scars were interviewed to obtain information on each child's demographics and the burn event, among others. Burn repeaters were compared with non-repeaters (children burned just once). Of 630 children identified with burns, 20 (3.2 per cent) had been burned twice. This statistic is significantly lower than expected from the known burn prevalence of 6.1 per cent in the region (P < 0.01). Burn repeaters included nine (45 per cent) children aged 24-35 months, 11 (55 per cent) males, and 9 (45 per cent) rural residents. The mean time interval between repeat burns was 9.6 months. While different mechanisms caused the two burns in 14 children, six were burned by the same mechanism. None of the demographic and socioenvironmental variables examined was significantly associated with burn repetition. It is concluded that since burn repetitions are low and share similar epidemiological characteristics with first-time burns, prevention efforts need not address repeat burns separately from burns in general.

Age Distribution↗

PubMed2025

Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it?

PURPOSE: Genomics research enrolling undiagnosed patients can provide answers for one-third of participants, and more can be diagnosed through future reanalysis. The long-term value for participants has raised questions of the sustainability of these studies, but the meaning, goals, and best practices for sustainability remain unclear. METHODS: We conducted semistructured interviews with researchers leading studies enrolling undiagnosed patients in the United States and Canada and used thematic content analysis to summarize key themes. RESULTS: Researchers lacked consensus regarding what sustainability was actually intended to sustain, variably referencing study procedures, personnel, data access, and participant recontact. However, the primary driver of sustainability was widely shared as the perceived obligation to continue to search for answers for undiagnosed participants. Proposed sustainability strategies included diversifying funding sources, developing centralized data infrastructure, and building collaborations across disciplines and institutions. Researchers also emphasized the need to address ethical concerns, to integrate research with clinical care, and for leadership from research funders to guide these efforts. CONCLUSION: Although genomics researchers perceived continued obligations to undiagnosed participants, they also lacked a shared understanding of the goals of sustainability and called for coordinated efforts to develop centralized infrastructure that integrated research and clinical care.

Humans↗

PubMed2006

The effect of misclassification errors on case mix measurement.

Case mix systems have been implemented for hospital reimbursement and performance measurement across Europe and North America. Case mix categorizes patients into discrete groups based on clinical information obtained from patient charts in an attempt to identify clinical or cost difference amongst these groups. The diagnosis related group (DRG) case mix system is the most common methodology, with variants adopted in many countries. External validation studies of coding quality have confirmed that widespread variability exists between originally recorded diagnoses and re-abstracted clinical information. DRG assignment errors in hospitals that share patient level cost data for the purpose of establishing cost weights affects cost weight accuracy. The purpose of this study is to estimate bias in cost weights due to measurement error of reported clinical information. DRG assignment error rates are simulated based on recent clinical re-abstraction study results. Our simulation study estimates that 47% of cost weights representing the least severe cases are over weight by 10%, while 32% of cost weights representing the most severe cases are under weight by 10%. Applying the simulated weights to a cross-section of hospitals, we find that teaching hospitals tend to be under weight. Since inaccurate cost weights challenges the ability of case mix systems to accurately reflect patient mix and may lead to potential distortions in hospital funding, bias in hospital case mix measurement highlights the role clinical data quality plays in hospital funding in countries that use DRG-type case mix systems. Quality of clinical information should be carefully considered from hospitals that contribute financial data for establishing cost weights.

Diagnosis-Related Groups↗

PubMed2026

Diverse structures of mcr-10-bearing plasmids and high colistin resistance in Enterobacter cloacae complex clinical isolates from South Korea.

BACKGROUND: The emergence of mcr-mediated colistin resistance in Enterobacter cloacae complex (ECC) poses a significant threat to antimicrobial therapy. Among mcr variants, mcr-10 has been identified in various environments, but its genetic diversity, structural context, and functional role in colistin resistance remain unclear. METHODS: We investigated 183 ECC isolates and identified 60 colistin-resistant strains through minimum inhibitory concentration (MIC) testing. The presence of mcr-10 was screened using reference genomes from NCBI, and whole plasmid sequencing was conducted on mcr-10-positive isolates. The genetic environment of mcr-10 was analyzed via synteny and structural annotation. RESULTS: Whole-plasmid sequencing of eight mcr-10-positive ECC isolates identified three replicon types among the mcr-10-harboring plasmids: IncFIB (n=3), IncFII (n=3), and IncFII/IncFIB (n=2). Although all plasmids shared the xerC-mcr-10 cassette, they lacked a conserved backbone and showed diverse genetic contexts with variable insertion sequences near mcr-10, indicating marked structural heterogeneity. No additional antimicrobial resistance genes were detected on these plasmids. When introduced into E. coli DH5α, the plasmids increased colistin MICs only modestly, whereas representative plasmids transferred into colistin-susceptible E. roggenkampii and E. kobei conferred high-level resistance comparable to that of the parental mcr-10-positive isolates. Consistently, qRT-PCR showed higher mcr-10 expression in ECC transformants than in E. coli under colistin exposure, supporting a hostdependent effect on mcr-10-mediated colistin resistance. CONCLUSION: These findings highlight the diversity of mcr-10-carrying plasmids and suggest that mcr-10-mediated colistin resistance is shaped by the host genetic background. Further studies are needed to clarify the mechanisms underlying mcr-10 expression.

Colistin↗

PubMed2003

Serotonergic activity measured by platelet [3H]paroxetine binding in patients with eating disorders.

Most of the evidence from pharmacological studies supports the hypothesis of a serotonergic (5-HT) dysregulation in eating disorders (ED), though a specific alteration related to the major ED subtypes, anorexia (AN) and bulimia nervosa (BN), has not been identified yet, possibly because of changes over time in ED nosology. The aim of the present study was to verify whether differences in serotonergic activity, measured by platelet [3H]paroxetine binding, would validate current ED classification. Platelet [3H]paroxetine binding was investigated in 26 patients with eating disorders diagnosed in accord with DSM-IV criteria (AN, n=11; BN, n=15) and 26 normal weight controls of comparable age; ED symptomatology was assessed by the Diagnostic Schedule for Eating Disorders. ED patients had significantly lower B(max) values than controls (288.5+/-109.2 vs. 1396.8+/-251.3 fmol/mg), whereas the K(d) was not significantly altered (0.12+/-0.13 and 0.12+/-0.05 nM, respectively). Among patients, differences in B(max) were related neither to DSM-IV subtypes nor to clinical variables such as presence of binge-eating, purging, impulsive behaviors, or symptoms of depression. Although ED patients share a dysregulation in serotonergic activity, DSM-IV subtype classification was not validated by [3H]paroxetine binding, and hence does not correspond to a specific 5-HT profile.

Adult↗

PubMed1999

Structure and alternative splicing of the gene encoding the human beta1 subunit of voltage dependent calcium channels.

The structure of the gene encoding the human brain beta1 subunit of voltage dependent calcium channels (CACNB1) was determined by comparison of its genomic sequence with beta1 cDNA sequence. CACNB1 is distributed over 25 kb and contains 13 exons. Alternative splicing of CACNB1 RNA occurs within the central domain at exon 7, and the 3' domain at exon 13, producing the variably expressed beta1a, beta1b and beta1c isoforms. Exon/intron boundaries and exon lengths are conserved for the nine exons shared by the beta1 and related brain beta3 and beta4 genes.

Alternative Splicing↗