Use of surname models in human population biology: a review of recent developments

Since 1985, when a bibliography concerning studies on surnames and genetic structure appeared, the number of publications on this subject has increased a thousandfold. New topics and uses have been added, but large gaps in knowledge remain. Only studies on isonymy in cities of nation states for recent times are well covered, and most studies are on populations that were selected because they are isolated and not because they are typical. This review, although not exhaustive, covers the literature published since 1985.     

Genomic disorders on 22q11

The 22q11 region is involved in chromosomal rearrangements that lead to altered gene dosage, resulting in genomic disorders that are characterized by mental retardation and/or congenital malformations. Three such disorders-cat-eye syndrome (CES), der(22) syndrome, and velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS)-are associated with four, three, and one dose, respectively, of parts of 22q11. The critical region for CES lies centromeric to the deletion region of VCFS/DGS, although, in some cases, the extra material in CES extends across the VCFS/DGS region. The der(22) syndrome region overlaps both the CES region and the VCFS/DGS region. Molecular approaches have revealed a set of common chromosome breakpoints that are shared between the three disorders, implicating specific mechanisms that cause these rearrangements. Most VCFS/DGS and CES rearrangements are likely to occur by homologous recombination events between blocks of low-copy repeats (e.g., LCR22), whereas nonhomologous recombination mechanisms lead to the constitutional t(11;22) translocation. Meiotic nondisjunction events in carriers of the t(11;22) translocation can then lead to offspring with der(22) syndrome. The molecular basis of the clinical phenotype of these genomic disorders has also begun to be addressed. Analysis of both the genomic sequence for the 22q11 interval and the orthologous regions in the mouse has identified >24 genes that are shared between VCFS/DGS and der(22) syndrome and has identified 14 putative genes that are shared between CES and der(22) syndrome. The ability to manipulate the mouse genome aids in the identification of candidate genes in these three syndromes. Research on genomic disorders on 22q11 will continue to expand our knowledge of the mechanisms of chromosomal rearrangements and the molecular basis of their phenotypic consequences.     

Analysis and 3D reconstruction of heterogeneity in malignant brain tumors: an interdisciplinary case study using a novel computational visualization approach

OBJECTIVE: To explore how a multidisciplinary approach, combining modern visualization and image processing techniques with innovative experimental studies, can augment the understanding of tumor development. STUDY DESIGN: We analyzed histologic sections of a microscopic brain tumor and reconstructed these slices into a 3D representation. We processed these slices to: (1) identify tumor boundaries, (2) isolate proliferating tumor cells, and (3) segment the tumor into regions based on the density of proliferating cells. We then reconstructed the 3D shape of the tumor using a constrained deformable surface approach. RESULTS: This novel method allows the analyst to (1) see specific properties of histologic slices in the 3D environment with animation, (2) switch 2D "views" dynamically, and (3) see relationships between the 3D structure and structure on a plane. CONCLUSION: Using this method to analyze a specific "case," we were also able to shed light on the limitations of a widely held assumption about the shape of expanding microscopic solid tumors as well as find more indications that such tumors behave as adaptive biosystems. Implications of these case study results, as well as future applications of the method for tumor biology research, are discussed.     

Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in ovine fetal pulmonary circulation: a double labeling immunohistochemical study

Endothelial nitric oxide synthase (eNOS) or NOS-III in the endothelium catalyzes production of nitric oxide (NO). Nitric oxide diffuses freely into vascular smooth muscle, where it activates soluble guanylate cyclase (sGC) to produce guanosine 3',5'-cyclic monophosphate (cGMP) and causes vasorelaxation. The NO/cGMP pathway is an important signaling pathway in the control of perinatal pulmonary circulation. An exact colocalization of NOS-III in the pulmonary endothelium and sGC in the vascular smooth muscle was demonstrated using a double immunolabeling technique. The sGC immunoreactivity was higher in resistant pulmonary vessels and veins than in conduit arteries, whereas NOS-III immunoreactivity was higher in conduit arteries than in veins. These results demonstrated anatomically in situ a paracrine role of NOS-III and sGC in the regulation of fetal pulmonary circulation and suggested a heterogeneous distribution of NOS-III and sGC within fetal ovine pulmonary vasculature. Our results provided an anatomic basis that supported previous functional studies on perinatal control of pulmonary circulation.     

Heterogeneous distribution of type I nitric oxide synthase in pulmonary vasculature of ovine fetus

The nitric oxide/guanosine 3',5'-cyclic monophosphate pathway plays an essential role in mediating pulmonary vasodilation at birth. Small resistance arteries in the fetal lung are vessels of major significance in the regulation of pulmonary vascular tone. The present study is to determine that type I nitric oxide synthase (NOS-I) is present in ovine fetal pulmonary vasculature and that NOS-I is distributed heterogeneously in ovine fetal pulmonary circulation. We used reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and NOS-I immunohistochemistry to localize NOS-I in fetal sheep lungs and showed a colocalization for NADPH-d activity with NOS-I immunoreactivity. Strong NOS-I immunoreactivity was observed exclusively in the endothelium of the terminal bronchiole and respiratory bronchiole-associated arteries. As a comparison, adult sheep lung did not show positive immunoreactivity in the pulmonary endothelium. NOS-I was absent in the umbilical or systemic arteries from the ovine fetus, whereas abundant NOS-III immunoreactivity was present in these arteries. We conclude that NOS-I is present uniquely in the ovine fetal pulmonary circulation as opposed to the adult pulmonary or the fetal systemic circulation. NOS-I is distributed heterogeneously in the ovine pulmonary vasculature. We speculate that NOS-I plays an active role in the regulation of perinatal pulmonary circulation.     

Awareness of Sensorimotor Adaptation to Visual Rotations of Different Size

Previous studies on sensorimotor adaptation revealed no awareness of the nature of the perturbation after adaptation to an abrupt 30° rotation of visual feedback or after adaptation to gradually introduced perturbations. Whether the degree of awareness depends on the magnitude of the perturbation, though, has as yet not been tested. Instead of using questionnaires, as was often done in previous work, the present study used a process dissociation procedure to measure awareness and unawareness. A naïve, implicit group and a group of subjects using explicit strategies adapted to 20°, 40° and 60° cursor rotations in different adaptation blocks that were each followed by determination of awareness and unawareness indices. The awareness index differed between groups and increased from 20° to 60° adaptation. In contrast, there was no group difference for the unawareness index, but it also depended on the size of the rotation. Early adaptation varied between groups and correlated with awareness: The more awareness a participant had developed the more the person adapted in the beginning of the adaptation block. In addition, there was a significant group difference for savings but it did not correlate with awareness. Our findings suggest that awareness depends on perturbation size and that aware and strategic processes are differentially involved during adaptation and savings. Moreover, the use of the process dissociation procedure opens the opportunity to determine awareness and unawareness indices in future sensorimotor adaptation research.     

Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality

The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor alpha (PPARalpha). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at various time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Pparalpha indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners.     

<Emphasis Type="Italic">Wolinella succinogenes</Emphasis> response to ox-bile stress

The bacterium Wolinella succinogenes is the only known species of its genus. It was first isolated from cow ruminal fluid, and in cattle, it dwells in the reticulum and rumen compartments of the stomach. The global protein response of W. succinogenes to ox-bile was investigated with the aim to understand bile-tolerance mechanisms of the bacterium. Bacteria were grown in liquid media supplemented with different bile concentrations to determine its effects on growth and morphology. Proteomic analyses served to identify 14 proteins whose expression was modulated by the presence of 0.2% bile. Quantitative real-time PCR analyses of the expression of selected genes were employed to obtain independent confirmation of the proteomics data. Proteins differentially expressed revealed metabolic pathways involved in the adaptation of W. succinogenes to bile. The data suggested that bile stress elicited complex physiological responses rather than just specific pathways, and identified proteins previously unknown to be involved in the adaptation of bacteria to bile.     

Identification of an altered peptide ligand based on the endogenously presented, rheumatoid arthritis-associated, human cartilage glycoprotein-39(263-275) epitope: an MHC anchor variant peptide for immune modulation

We sought to identify an altered peptide ligand (APL) based on the endogenously expressed synovial auto-epitope of human cartilage glycoprotein-39 (HC gp-39) for modulation of cognate, HLA-DR4-restricted T cells. For this purpose we employed a panel of well-characterized T cell hybridomas generated from HC gp-39-immunized HLA-DR4 transgenic mice. The hybridomas all respond to the HC gp-39(263-275) epitope when bound to HLA-DR4(B1*0401) but differ in their fine specificities. First, the major histocompatibility complex (MHC) and T-cell receptor (TCR) contact residues were identified by analysis of single site substituted analogue peptides for HLA-DR4 binding and cognate T cell recognition using both T hybridomas and polyclonal T cells from peptide-immunized HLA-DR4 transgenic mice. Analysis of single site substituted APL by cognate T cells led to identification of Phe265 as the dominant MHC anchor. The amino acids Ala268, Ser269, Glu271 and Thr272 constituted the major TCR contact residues, as substitution at these positions did not affect HLA-DR4(B1*0401) binding but abrogated T cell responses. A structural model for visualisation of TCR recognition was derived. Second, a set of non-classical APLs, modified at the MHC key anchor position but with unaltered TCR contacts, was developed. When these APLs were analysed, a partial TCR agonist was identified and found to modulate the HC gp-39(263-275)-specific, pro-inflammatory response in HLA-DR4 transgenic mice. We identified a non-classical APL by modification of the p1 MHC anchor in a synovial auto-epitope. This APL may qualify for rheumatoid arthritis immunotherapy.