Immune down-regulation and peripheral deletion of CD8 T cells does not require TNF receptor-ligand interactions nor CD95 (Fas, APO-1)

TNF receptor-ligand interactions and CD95 (Fas / APO-1) have been demonstrated to be involved in activation-induced death of mature T cells. Here, we examined the role of these molecules in the murine model of lymphocytic choriomeningitis virus (LCMV) infection using LCMV TCR transgenic (tg) mice lacking TNF, TNF receptor I (TNFR1), CD95 or both TNFR1 and CD95. This report demonstrates that neither TNF receptor-ligand interactions nor CD95 was required for down-regulation of LCMV-specific CD8 T cells following acute LCMV infection in vivo. Even LCMV-specific CD8 T cells lacking both TNFR1 and CD95 molecules declined after the acute phase of the infection with normal kinetics. Furthermore, peripheral deletion of LCMV-specific CD8 T cells induced by LCMV peptide injection or by adoptive transfer of tg spleen cells expressing the corresponding LCMV epitope was not impaired in mice lacking TNF, TNFR1 and / or CD95. Our data speak against an indispensable role of these molecules in antigen-induced apoptosis of CD8 T cells in vivo and suggest that T cell homeostasis after antigen challenge is controlled by additional mechanisms.     

Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000 Copyright 2000 Wiley-Liss, Inc.     

Inhibition of murine macrophage IL-12 production by natural and synthetic DNA

DNA is a complex macromolecule whose immunological properties vary with sequence and structure. To determine whether DNA can inhibit immune responses, the effects of mammalian DNA and synthetic phosphodiester (Po) and phosphorothioate (Ps) oligonucleotides (ODNs) on IL-12 production were tested using murine macrophages. With bacterial DNA as a stimulant, calf thymus DNA and human placenta DNA blocked IL-12 production by splenic and bone marrow macrophages. A (dG)(30) Po ODN and all single-base Ps 30 mer ODNs were also effective inhibitors. The Ps ODNs also blocked IL-12 production induced by lipopolysaccharide (LPS) and a stimulatory Ps ODN. With the J774 cell line, single-base Ps ODNs inhibited IL-12 production induced by bacterial DNA, LPS, and a stimulatory Ps ODN. Together, these results indicate that DNA has inhibitory properties, suggesting that mammalian DNA could limit immune activation during inflammation and counteract the effects of bacterial DNA.     

MOTHERS’ PERCEPTIONS OF NEIGHBORHOOD DISORDER ARE ASSOCIATED WITH CHILDREN'S HOME ENVIRONMENT QUALITY

This study examines how low–income mothers' perceptions of their neighborhoods are associated with the home environments they provide for their young children. The connection between neighborhoods and homes is important since they are nested systems that are critical to children's healthy development. Women's perception of their neighborhoods may affect the way they set up their homes and interact with their young children. Given that various women may perceive the same neighborhood differently, this study uses subjective, rather than typical objective measures of neighborhood disadvantage. After controlling for maternal background characteristics, including stress and depression, these data find that the more women perceive their neighborhood to be disordered, the less likely they are to provide high–quality home environments and be responsive to their infants. Establishing a link between neighborhood and home environments is important and illuminates avenues for potentially improving the contexts of young children's lives.     

Apparent replication of suggestive linkage on chromosome 16 in the NIMH genetics initiative bipolar pedigrees

Analyses of a replication sample of families collected as part of the National Institute of Mental Health (NIMH) Genetics Initiative for bipolar disorder provide further evidence for linkage to a region of chromosome 16. Families who had a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SABP) first-degree relative were ascertained for the purpose of identifying genes involved in bipolar affective disorder. A series of hierarchical models of affected status was used in linkage analyses. Initial genetic analyses of chromosomes 3, 5, 15, 16, 17, and 22, completed at Indiana University in 540 subjects from 97 families, suggested evidence of linkage to chromosomes 5, 16, and 22 [Edenberg et al., 1997: Am J Med Genet 74:238-246]. Genotyping was subsequently performed on these chromosomes in a replication sample of 353 individuals from 56 families. Nonparametric linkage analyses were performed using both affected relative and sibling pair methods. Analyses in the new sample on chromosome 16, using the broadest model of affected status, corroborate previously reported suggestive linkage to the marker D16S2619. Combining the initial and replication samples further increased the evidence of linkage to this region, with a peak lod score of 2.8.     

Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer

We previously found LOXL4 to be alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. LOXL4 splice variants were predominantly or exclusively expressed in effusion specimens from ovarian and breast carcinoma patients, and were absent in primary carcinomas. In the present study, LOXL4 full-length or splice variants were overexpressed in ES-2 and MDA-MB-231 cells and their invasive and metastatic potential and microRNA expression profile were evaluated. ES-2 cells were further injected into SCID mice ovaries and the extent of tumor progression and metastases formation were compared. We show that both splice variants have a positive effect on the metastatic potential of cells in vitro and on tumor progression in vivo. In contrast, full-length LOXL4 is not pro-metastatic, and may even be considered as a tumor suppressor. In addition, we show that LOXL4 is a possible splicing target of the oncogenic splicing factors SRSF1 and hnRNP A1. In conclusion, our results point to a significant role for LOXL4 alternative splicing in tumor progression.     

UMMPerfusion: an Open Source Software Tool Towards Quantitative MRI Perfusion Analysis in Clinical Routine

To develop a generic Open Source MRI perfusion analysis tool for quantitative parameter mapping to be used in a clinical workflow and methods for quality management of perfusion data. We implemented a classic, pixel-by-pixel deconvolution approach to quantify T1-weighted contrast-enhanced dynamic MR imaging (DCE-MRI) perfusion data as an OsiriX plug-in. It features parallel computing capabilities and an automated reporting scheme for quality management. Furthermore, by our implementation design, it could be easily extendable to other perfusion algorithms. Obtained results are saved as DICOM objects and directly added to the patient study. The plug-in was evaluated on ten MR perfusion data sets of the prostate and a calibration data set by comparing obtained parametric maps (plasma flow, volume of distribution, and mean transit time) to a widely used reference implementation in IDL. For all data, parametric maps could be calculated and the plug-in worked correctly and stable. On average, a deviation of 0.032 ± 0.02 ml/100 ml/min for the plasma flow, 0.004 ± 0.0007 ml/100 ml for the volume of distribution, and 0.037 ± 0.03 s for the mean transit time between our implementation and a reference implementation was observed. By using computer hardware with eight CPU cores, calculation time could be reduced by a factor of 2.5. We developed successfully an Open Source OsiriX plug-in for T1-DCE-MRI perfusion analysis in a routine quality managed clinical environment. Using model-free deconvolution, it allows for perfusion analysis in various clinical applications. By our plug-in, information about measured physiological processes can be obtained and transferred into clinical practice.