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To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.

Antisera directed against histocompatibility-2 antigens of the mouse suppress the formation of spleen colonies by pluripotent hemopoietic stem cells. Of antisera which are specific for subregions of the H-2 complex, only those which contain anti-H-2K or anti-H-2D activity are effective. Specific anti-Ia sera do not react with the stem cell. If the titer of the CFU-s suppressive effect of the antisera is compared to their toxicity to spleen lymphocytes, it can be concluded that CFU-s express antigens in the same density as spleen lymphocytes. The amount of H-2 antigens expressed on the surface of CFU-s is independent of its rate of proliferation. Chemicals/CAS: Epitopes; H-2 Antigens; Immune Sera; Papain, EC 3.4.22.2

Allogeneic demineralized bone matrix (DBM) has been used extensively as a clinical graft material because of its inherent osteoinductive and osteoconductive properties. There is continued debate over the acceptable age range of donors for bone and whether the effectiveness of the tissue as a graft is influenced by gender. Contradictory evidence has been obtained with DBM prepared from both animals and humans. The goal of the present investigation was to evaluate the effect of donor age and gender on the osteoinductivity of DBM prepared from human donors [male (133) and female (115) donors grouped in 10-year age brackets up to 85 years] with a statistically relevant sample size using the athymic rat ectopic bone formation model. Among males, there was a statistically significant linear association between age and osteoinductivity value (p

The current study aimed to assess the topology of the nuclear receptor (NR) superfamily in normal prostate epithelial cells and its distortion in prostate cancer. Both in vitro and in silico approaches were utilized to profile NRs expressed in non-malignant RWPE-1 cells, which were subsequently investigated by treating cells with 132 binary NR ligand combinations. Nine significant cooperative interactions emerged including both superadditive [22(R)-hydroxycholesterol and eicosatetraenoic acid] and subadditive [1α,25(OH)2D3 and chenodeoxycholic acid] cellular responses, which could be explained in part by cooperative control of cell-cycle progression and candidate gene expression. In addition, publicly available data were employed to assess NR expression in human prostate tissue. Common and significant loss of NR superfamily expression was established in publicly available data from prostate tumors, in part predicting parallel distortion of targeting microRNA. These findings suggest that the NR superfamily in the prostate cooperatively integrates signals from dietary, hormonal and metabolic cues, and is significantly distorted in prostate cancer.

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.

Mineralization and integrity of the bone graft mass were evaluated among patients having posterolateral fusion. Grafting consisted of a composite of Grafton and "local" autologous bone (n=56) or iliac crest autograft alone (n=52). Mineralization was rated radiographically at baseline and at 3, 6, 12, and 24 months. Integrity was judged as fused or not fused. Mineralization ratings did not differ significantly between groups at any postoperative interval (P values of .25-1 .00). The percentage of patients fused was similar in both groups (60% and 56% for Grafton and controls, respectively; P=.83). Fifteen control patients reported donor site pain. These findings warrant further evaluation of this composite.

The patterns of proliferation of C1498 mouse acute leukemic cells have been studied using the diffusion chamber technique of cell culture. These malignant cells grow to the same maximal cell concentration irrespective of initial cell input. Leukemic cells proliferate equally well with or without the stimulus of prior host irradiation. When cells cultured for several days are diluted to the original input concentration and recultured, they rapidly proliferate back to maximal cell number. All of these findings are in sharp contrast to the behavior of granulocytes from normal mouse marrow grown in the same culture system. Co-culutre of equal numbers of normal marrow cells and leukemic cells results in virtually complete inhibition of normal marrow cells and leukemic cells results in virtually complete inhibition of normal granulocyte growth. These experiments provide a means of studying malignant growth of leukemic cells, as compared to the controlled growth and differentiation of normal granulocytes, and mechanisms by which leukemic cells suppress normal granulocyte development.

Two software tools are described that are designed to facilitate software development for microcontrollers. One is a mid-level programming language called Pascal/48 and the other is a circuit simulation system. Pascal/48 is designed to give the programmer many of the advantages of a high-level language, but also provide access to all of the hardware of the Intel MCS-48 series of microcontrollers. The circuit simulation system combines many of the advantages of simulation and emulation. It provides a software testing environment in which many more software functions can be tested than with conventional simulators. The system integrates an instruction-set simulator with simulators for other devices. They operate in parallel and are synchronized by a clock that records simulated time. I/O lines of the microcontroller can be linked to other components so that complete circuits can be simulated. Displays are provided of the internal and external state of the simulated circuit, and of the Pascal/48 program being executed. They are updated as simulated execution proceeds using the screen updating facilities of ASCII terminals. Simulation can be continuous, single step, or execution can be reversed (i.e. instructions are ‘unexecuted’).

Several main dimensions were identified by factor analysis of political attitudes of secondary schoolboys in Northern Ireland. Attitudinal responses of 303 Catholics and 266 Protestants were used in the present study. A composite sub-sample of 260 boys was also derived to give a roughly representative sample of secondary schoolboys in Northern Ireland. Among the key dimensions identified by factor analysis of these samples were: the degree of acceptance of members of the opposite communal group for general social interaction, acceptance or rejection of the other group for more intimate association, the degree of approval of violent behaviour, the amount of positive sentiment toward the government, and the degree of support for the ideological assumptions of Unionism. Attitude scales were derived to represent these factors and tested for reliability. Reasonable reliability was demonstrated for scales measuring most of the above dimensions, though only a composite scale to measure intergroup attitudes had r...

In a survey conducted throughout the Republic of Ireland in 1978 almost 700 people of pensionable age who lived alone were interviewed in their homes. The most frequently occurring descriptions of feelings about living alone were investigated against fifty-eight background features. From controlled multi-variate analysis three background features were found to predict much of the variance in how elderly people felt about living alone: general life satisfaction; housing satisfaction; and reasons for living alone. These predictors were used to identify groups of elderly people who held the most negative views. Seven tenths of the elderly surveyed had a very positive attitude to living alone, however. The findings underline the inadequacy of objective indicators in predicting how people feel about life.

Leukemic AKR mouse spleen cells suppress normal AKR anti-sheep erythrocyte antibody responses in vitro . Treatment of leukemic spleen cells with DNase I prior to coculture with normal AKR cells abrogates their suppressive ability. Treatment of leukemic cells with a wide range of DNase I concentrations has no effect on the viability of these cells as measured by incorporation of [ 3 H]thymidine or by eosin dye exclusion. When the activating divalent cations required for DNase I action are functionally removed in the enzyme treatment medium by chelation with EDTA, the ability of DNase I to abrogate suppression is abolished. Furthermore, the effects of DNase I in overcoming suppression are not able to be mimicked by trypsin, Pronase, or ribonuclease. These results are consistent with the existence of a population of cells in the leukemic spleen that expresses a form of membrane-associated DNA that functions in the suppression of normal antibody responses. The existence of such a population was shown by treating leukemic spleen cells with anti-single-stranded-DNA and then passing them through an anti-immunoglobulin immunoadsorption column. Approximately 15% of the leukemic cells are retained on the column and can be specifically eluted with the normal immunoglobulin. The cells of this enriched population when cocultured with normal spleen cells exhibit a 10-fold greater suppressive ability than unfractionated cells. Thus, there exists in the spleens of overtly leukemic AKR mice a population of cells expressing a form of DNA on their surfaces that in some manner is necessary for immunosuppression.

Giant pigmented nevi afflict the patient not only with an unsightly cosmetic defect but also with the hazard of possible conversion to cancer. Such a nevus, extending over the back of an 18-year-old girl, was removed by surgical excision. Several hundred smaller nevi were removed from other parts of her body surface. Three separate operative procedures were required; the first was to remove the nevi from the right side of her body and prepare a skin donor site, the second to remove part of the large nevus and the smaller ones from her left side, and a third for complete excision of the giant nevus. Almost all the skin grafts were successful, and no malignant changes were found in any of the nevi excised.