Large-scale identification of mammalian proteins localized to nuclear sub-compartments

Many nuclear components participating in related pathways appear concentrated in specific areas of the mammalian nucleus. The importance of this organization is attested to by the dysfunction that correlates with mis-localization of nuclear proteins in human disease and cancer. Determining the sub-nuclear localization of proteins is therefore important for understanding genome regulation and function, and it also provides clues to function for novel proteins. However, the complexity of proteins in the mammalian nucleus is too large to tackle this on a protein by protein basis. Large-scale approaches to determining protein function and sub-cellular localization are required. We have used a visual gene trap screen to identify more than 100 proteins, many of which are normal, located within compartments of the mouse nucleus. The most common discrete localizations detected are at the nucleolus and the splicing speckles and on chromosomes. Proteins at the nuclear periphery, or in other nuclear foci, have also been identified. Several of the proteins have been implicated in human disease or cancer, e.g. ATRX, HMGI-C, NBS1 and EWS, and the gene-trapped proteins provide a route into further understanding their function. We find that sequence motifs are often shared amongst proteins co-localized within the same sub-nuclear compartment. Conversely, some generally abundant motifs are lacking from the proteins concentrated in specific areas of the nucleus. This suggests that we may be able to predict sub-nuclear localization for proteins in databases based on their sequence.     

Linkage studies in spinocerebellar ataxia (SCA)

Data are now available on 9 pedigrees in detail and 4 pedigrees as lod scores only. Linkage to HLA is significant (? = 5.53 at recombination rates of 0.223 in males and 0.327 in females). Tight linkage is excluded. Nine pedigrees which appear to be typical olivopontocerebellar atrophy (OPCA I) have recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees are clinically atypical or include discrepant data and give no evidence for linkage. The symbol SCA1 is proposed for a locus on chromosome 6 (loosely linked to HLA), at which at least one allele produces OPCA I (Menzel type). It is not yet clear whether other clinical types are determined by alleles at different loci, although this is suggested by several pedigrees, including a Danish pedigree of OPCA with dementia. Linkage evidence will be decisive in delineating the ataxias.     

Oculoauriculovertebral anomaly: Segregation analysis

Seventy-four families of probands with oculoauriculovertebral anomaly were evaluated, including 116 parents and 195 off-spring. Relatives were examined to identify ear malformations, mandibular anomalies, and other craniofacial abnormalities. For segregation analysis using POINTER, selection of the sample was consistent with single as-certainment. Different population liabilities were used for probands and relatives, because affection was narrowly defined for probands and broadly defined for relatives. The hypothesis of no genetic transmission was rejected. The evidence favored autosomal dominant inheritance; recessive and polygenic models were not distinguishable. © 1992 Wiley-Liss, Inc.     

Pathologic features of extraosseous Ewing's sarcoma: a report from the Intergroup Rhabdomyosarcoma Study

Eighty-four cases of extraosseous Ewing's sarcoma (EOE) were found during the pathology review of the Intergroup Rhabdomyosarcoma Study I and II. Patients commonly presented during or after adolescence with the most common primary sites including the trunk, extremities, and retroperitoneum. Males were slightly more affected. Histologic sections of 74 tumors in the pathology repository were re-reviewed with attention to rosette formation (positive in 18 cases) and glycogen deposition (++ in 21, + in 36, +/- in 11, and - in 2 of 70 cases examined). Fourteen tumors (7 with rosettes and 7 without) were selected for immunohistochemical and ultrastructural studies, and 13 showed single or multiple neural markers (neuron-specific enolase in 8, S-100 protein in 6, and neurosecretory-type granules in 9). These possible cases of neural EOE could be divided into three subgroups: tumor with bidirectional neuroblastic and schwannian differentiation (5 cases), tumor with monodirectional neuroblastic differentiation (7 cases), and tumor with monodirectional schwannian differentiation (1 case). EOE with a neural nature may be categorized into a spectrum of peripheral primitive neuroectodermal tumors. Clinical, histopathologic, and biologic differences between this disease and conventional sympathetic neuroblastoma are discussed.     

Psychologic aspects of lactation

Lactation is a psychological phenomenon. This is indicated by the fact that breastfeeding has declined so rapidly in recent years in western countries. Successful breastfeeding depends on maternal factors, infant response to breastfeeding, and various psychophysiological factors, which are, in turn, affected by the maternal and infant variables. Studies have shown generally that women who have more positive or stronger maternal attitudes and those who had more positive obstetric experiences are more likely to breastfeed. They are also more likely to succeed and to continue with breastfeeding. Women who respond sexually to the process of breastfeeding are more likely to succeed with it. Women are more likely to breastfeed if attitudes in the general society are favorable to it. 2 psychosomatic mechanisms--the milk-ejection reflex and the suckling stimulation--are discussed in relation to the success of the lactation process. Through these mechanisms, the previously discussed psychological factors may affect the actual production of milk.     

Viral load responses to HAART is an independent predictor of a new AIDS event in late stage HIV infected patients: prospective cohort study

Background  

A sizeable number of HIV-infected patients receiving HAART do not maintain prolonged virologic suppression. We evaluated long-term HIV viral load (VL) responses to HAART as a risk factor for AIDS events (AE) that is independent of CD4 responses.     

A potential role for beta- and gamma-crystallins in the vascular remodeling of the eye.

We demonstrate that expression of beta- and gamma-crystallins is associated with intraocular vessels during normal vascular development of the eye and also in the Nuc1 rat, a mutant in which the hyaloid vascular system fails to regress normally. Real-Time RT PCR, Western blot and metabolic labeling studies indicate an increased expression of beta- and gamma-crystallins in Nuc1 retina. The increased expression of crystallins was localized to the astrocytes surrounding the intraocular vessels. A similar pattern of crystallin expression was also observed in the retinal vessels during normal development. Cultured human astrocytes exposed to 3-nitropropionic acid, an established model of neuronal hypoxia, increased VEGF expression, as expected, but also increased expression of crystallins. Our data suggest that crystallins may function together with VEGF during vascular remodeling. Interestingly, in human PFV (persistent fetal vasculature) disease, where the hyaloid vasculature abnormally persists after birth, we show that astrocytes express both VEGF and crystallins.     

Microbial infections,immunomodulation, and drugs of abuse

The use of recreational drugs of abuse has generated serious health concerns. There is a long-recognized relationship between addictive drugs and increased levels of infections. Studies of the mechanisms of actions of these drugs became more urgent with the advent of AIDS and its correlation with abused substances. The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine, nicotine, and alcohol are described in this review. Recent studies of the effects of opiates or marijuana on the immune system have demonstrated that they are receptor mediated, occurring both directly via specific receptors on immune cells and indirectly through similar receptors on cells of the nervous system. Findings are also discussed that demonstrate that cocaine and nicotine have similar immunomodulatory effects, which are also apparently receptor mediated. Finally, the nature and mechanisms of immunomodulation by alcohol are described. Although no specific alcohol receptors have been identified, it is widely recognized that alcohol enhances susceptibility to opportunistic microbes. The review covers recent studies of the effects of these drugs on immunity and on increased susceptibility to infectious diseases, including AIDS.