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PubMed1996

CD34 selections from myeloma peripheral blood cell autografts contain residual tumour cells due to impurity, not to CD34+ myeloma cells.

Malignant cells in haemopoietic autografts can contribute to post-transplant relapse. Engraftment of myeloma patients with CD34+ peripheral blood progenitors selected from total autografts reduces the number of tumour cells infused by 2.7-4.5 logs. Residual tumour cells detected in CD34+ selected cells may be due to selection impurity or the existence of malignant CD34+ progenitors. In three patients we evaluated the CD34 purity and tumour load of total autografts, CD34+ progenitors selected with immunomagnetic beads and highly purified CD34+ progenitors obtained in two rounds of selection (combining magnetic with flow cytometry activated cell sorting) to determine the cause of residual tumour cells in CD34 selections. Using allele-specific oligonucleotides (ASO) complementary to the unique Ig heavy chain sequence (CDRIII region) of the malignant clone, semi-quantitative ASO-PCR was capable of detecting one malignant cell in 10(4)-10(5) normal white blood cells. Selection of CD34+ cells from bone marrow (BM) with approximately 20% malignant plasma cells resulted in a 1.4 log reduction of tumour burden. Using two-colour flow-cytometry we observed CD34-, BB4+ malignant plasma cells contaminating this CD34 selection. Prior to sorting, peripheral blood cell autografts (PBCA) contained approximately 0.1% malignant cells. Selection of > 99% pure CD34+ cells using immunomagnetic beads (Dynal) resulted in an approximate 2 log reduction of malignant cells, but residual tumour cells were still detectable. ASO-PCR detected no malignant cells in > 99.9% pure CD34+ peripheral blood progenitors obtained with two rounds of selection (combining magnetic with flow cytometry activated cell sorting). We conclude that CD34+ malignant cells are not detectable in myeloma PBCA and that residual tumour cells in CD34 selections are due to contaminating CD34-negative cells.

Antigens, CD34↗
PubMed2003

Evaluation of the de-selection of men who have had sex with men from blood donation in England.

BACKGROUND AND OBJECTIVES: The Blood Services of the UK permanently de-select men who have had sex with men (MSM) from donating blood. The rationale for this has been questioned. This article attempts to evaluate whether this selection criterion does contribute to blood safety. MATERIALS AND METHODS: Data about transfusion-transmissible infections, in particular about human immunodeficiency virus (HIV) infection, were used to evaluate whether de-selection of MSM meets the aims of donor selection. Models were constructed to estimate the risk of HIV-infectious donations entering the blood supply should this criterion be changed. RESULTS: Many assumptions were required to generate estimates of the risk of HIV infection entering the blood supply. The accuracy of the estimates is therefore uncertain and the probable ranges around the estimates were wide. However, by using the most probable assumptions, our models suggested that de-selection of MSM for 12 months since the last sexual contact, or complete removal of this selection criterion, would be expected to increase the risk of HIV-infectious donations entering the blood supply in England by approximately 60% (from the current risk of 0.45 per year to 0.75 per year) and 500% (to 2.5 per year), respectively. The increase in numbers of non-infected donations would be relatively small--less than 2% of donations. The probability of a relatively high frequency of other sexually transmissible blood-borne infections also currently favours maintaining permanent de-selection of MSM, irrespective of the risk of HIV-infectious donations. Current compliance with this selection criteria was estimated to be 95%. CONCLUSIONS: Based on current knowledge, accepting blood donations from MSM would probably increase the risk of transfusion-transmission of HIV and of other blood-borne infections. Good compliance with this criterion has contributed greatly to the safety of blood transfusions in England. Better communication about donor selection, to maintain and improve compliance with this and other selection criteria, is recommended. Other risk groups are gaining in relative importance for the risk of transfusion-transmitted HIV infection, and ongoing evaluation of all donor-selection criteria is also recommended.

Adolescent↗
PubMed2000

A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome.

BACKGROUND: The selectivity of proteinuria, introduced in clinical nephrology in 1960 and useful in predicting steroid responsiveness in nephrotic syndrome, found little place in clinical practice in subsequent decades, since its assessment did not appear to help predict histologic diagnosis or determine prognosis. The amount of proteinuria and the degree of tubulointerstitial damage appeared to be better predictors of functional outcome. A correlation between them has been found, referred to some toxicity of proteinuria on tubular cells, but so far no single feature or component of proteinuria has been identified as being responsible for this toxicity. METHODS: We evaluated 89 patients with nephrotic syndrome [9 with minimal change disease (MCD), 29 with primary focal segmental glomerulosclerosis (FSGS), and 51 with idiopathic membranous glomerulonephritis (MGN)] to determine if the selectivity of proteinuria was associated with tubulointerstitial damage. A semiquantitative grading of histologic lesions and qualitative evaluation of the "tubular" component of proteinuria expressed as a pattern of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and as fractional excretion of the low molecular weight (LMW) protein alpha1-microglobulin (FE alpha1m) were used. A second aim of the study was to assess the predictive value on functional outcome [remission or progression to chronic renal failure (CRF)] and response to therapy of the selectivity of proteinuria, considered alone and in combination with FE alpha1m. RESULTS: Proteinuria was classified as highly selective [selectivity index (SI) < or = 0.10, N = 15], moderately selective (SI > or = 0.11 < or = 0.20, N = 34), or nonselective (SI > or = 0.21, N = 40). A significant relationship was found between the SI and the histologic degree of tubulointerstitial damage (score 0 to 1 vs. score > or =2, P = 0.000), severity of the tubular component of proteinuria (mixed SDS-PAGE pattern with LMW proteins not lower than 23 kD vs. mixed pattern with LMW proteins up to 20 to 10 kD, P = 0.000), and FE alpha1m (values below vs. above a defined cut-off, P = 0.000). The functional outcome was evaluated in 60 patients with baseline normal renal function (serum creatinine 0.97 +/- 0.19 mg/dL). The patients with high, moderate, or nonselective proteinuria had 100, 50, and 29% of complete or partial remission (P = 0.0001) and 0, 25, and 35% of progression to CRF, respectively (P = 0.050). In 45 patients with moderately selective (N = 28) and nonselective (N = 17) proteinuria, according to some arbitrary cutoffs for FE alpha1m (MGN, < or = vs. > 0. 240% of creatinine clearance; FSGS and MCD, < or = vs. > 0.350%), the remission rate was 62 versus 6% in patients with FE alpha1m below or above the cutoffs (P = 0.0001), and progression to CRF was 7 and 69%, respectively (P = 0.0001). The response to therapy (complete or partial remission at the last observation), evaluated retrospectively in 40 patients, was 100, 67, and 33% in high, moderate, and nonselective proteinuria (P = 0.0002); in 30 patients with moderate and nonselective proteinuria, according to an FE alpha1m value that was < or = or > the cutoffs, the response rate was 75 versus 10% (P = 0.001). CONCLUSIONS: There is a significant relationship between selectivity of proteinuria and tubulointerstitial damage. Moreover, the selectivity of proteinuria has a predictive value on functional outcome. When proteinuria is highly selective, the tubulointerstitial damage is rather infrequent, and 100% of patients develop clinical remission. When proteinuria is moderately selective or nonselective, increasing numbers of patients develop tubulointerstitial damage; in these patients, the functional outcome and response to therapy is partly dependent on tubulointerstitial involvement, and the best predictor of functional outcome is the combination of SI and FE alpha1m.

Adolescent↗
PubMed1999

Comparison of class B scavenger receptors, CD36 and scavenger receptor BI (SR-BI), shows that both receptors mediate high density lipoprotein-cholesteryl ester selective uptake but SR-BI exhibits a unique enhancement of cholesteryl ester uptake.

Scavenger receptor BI (SR-BI) mediates the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without internalization and degradation of the HDL particle. The biochemical mechanism by which SR-BI mediates the selective uptake of HDL CE is poorly understood. Given that CE transfer will occur to some extent from HDL to protein-free synthetic membranes, one hypothesis is that the role of SR-BI is primarily to tether HDL close to the cell surface to facilitate CE transfer from the particle to the plasma membrane. In the present study, this hypothesis was tested by comparing the selective uptake of HDL CE mediated by mouse SR-BI (mSR-BI) with that mediated by rat CD36 (rCD36), a closely related class B scavenger receptor. Both mSR-BI and rCD36 bind HDL with high affinity, and both receptors mediate HDL CE selective uptake. However, SR-BI mediates selective uptake of HDL CE with a 7-fold greater efficiency than rCD36. HDL CE selective uptake mediated by rCD36 is dependent on HDL binding to the receptor, since a mutation that blocks HDL binding also blocks HDL CE selective uptake. These data lead us to hypothesize that one component of HDL CE selective uptake is the tethering of HDL particles to the cell surface. To explore the molecular domains responsible for the greater efficiency of selective uptake by mSR-BI, we compared binding and selective uptake among mSR-BI, scavenger receptor BII, and various chimeric receptors formed from mSR-BI and rCD36. The results show that the extracellular domain of mSR-BI is essential for efficient HDL CE uptake, but the C-terminal cytoplasmic tail also has a major influence on the selective uptake process.

Animals↗
PubMed2002

Isolex 300i CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: We have previously reported that repeated cycles of high-dose therapy (HDT), can be supported by unmanipulated autologous PBPC. Here we investigate whether purified CD34+ cells, obtained by immunomagnetic separation using the Isolex 300i device, can support such therapy. METHODS: Twenty-nine consecutive patients with metastatic breast cancer had PBPC mobilized and harvested following chemotherapy and G-CSF (10 microg/kg per day). Patients with > 4.0 x 10(6)/kg CD34+ cells in the apheresis product underwent CD34-selection using the Isolex 300i (v2.0) device. All cells collected were equally divided into three aliquots and cryopreserved. Patients who did not achieve this threshold had unmanipulated cells collected and stored. Patients subsequently received three cycles of HDT with paclitaxel (175 mg/m2), thiotepa (300 mg/m2) and either ifosfamide (10 g/m2) or cyclophosphamide (4 g/m2). It was intended for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e 1/3 for each cycle) and to compare hemopoietic recovery between patients receiving CD34-selected cells or unmanipulated cells. RESULTS: Thirteen of the 29 patients (45%) did not mobilize sufficient CD34+ cells to undergo CD34-selection. The remaining 16 patients underwent CD34-selection with a median purity of 84.3% (range: 16.3-96.1%) and yield of 34% (range: 1-60%). Fifteen of these patients proceeded to HDT and 42 of the planned 45 cycles were administered. Nine patients had all three HDT cycles supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (range: 0.04-3.01). Three of the 15 patients required infusion of 'back-up' unmanipulated cells because of delayed neutrophil recovery. Of the 13 patients whose PBPCs did not undergo CD34+ cell selection, 11 proceeded to HDT with a median of 3.2 x 10(6)/kg (range: 2.0-4.4) unselected cells infused per cycle and 31 of 33 planned cycles were delivered. When hemopoietic recovery was compared between cycles of HDT supported by CD34-selected (n = 34) and unmanipulated cells (n = 31), there was a modest slowing in the patients receiving CD34-selected cells; time to ANC > 1.0 x 10(9)/L = 11 days versus 10 days (P = 0.0122) and platelets > 20 x 10(9)/L = 14 days versus 13 days (P = 0.0009). No difference in recovery to 50 x 10(9)/L was observed (P = 0.54). CONCLUSION: We have demonstrated that Isolex 300i CD34-selected cells are capable of supporting multiple cycles of HDT. However, we were unable to acquire sufficient CD34+ cells to perform this processing in 45% (13/29) of patients and further improvements in yield are required to overcome the modest delay in neutrophil and platelet recovery.

Adult↗
PubMed2002

CliniMACS CD34-selected cells to support multiple cycles of high-dose therapy.

BACKGROUND: Traditionally, following high-dose therapy (HDT), unmanipulated autologous PBPC are infused. Alternatively, purified CD34+ cells can now be obtained by immunomagnetic separation using the CliniMACS device. Limited data currently exist examining hemopoietic recovery with such cells. METHODS: Ten patients with advanced breast cancer had PBPC mobilized with docetaxel (100 mg/m2) and G-CSF (10 microg/kg per day), harvested and processed using the CliniMACS CD34-selection device and equally divided into three aliquots for cryopreservation. Unmanipulated 'back-up' cells were also collected on a separate day of the same mobilization, divided into three and cryopreserved. Patients subsequently received three cycles of HDT with cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and paclitaxel (175 mg/m2). The intent was for patients to receive CD34-selected cells to support each of the three cycles of HDT (i.e., 1/3 for each cycle). If, however, hemopoietic recovery was delayed after Cycle 1, 1/3 of the unmanipulated cells were infused following Cycle 2 and the remaining CD34-selected cells (2/3) were used to support Cycle 3. RESULTS: PBPC from 10 patients underwent CD34-selection with a resulting median purity of 93% (range: 76-98%) and yield of 62% (range: 16-93%). Of the 10 patients, only two were able to be supported with CD34-selected cells for all three cycles of HDT. The remaining eight patients required unmanipulated 'back-up' cells to support Cycle 2. Three patients also required infusion of 'back-up' unmanipulated cells because of persistent neutropenia (n = 1) or thrombocytopenia (n = 2) following cycles initially supported by CD34-selected cells. The median number of CD34-selected cells (x 10(6)/kg) infused per cycle was 1.5 (0.7-2.6) (n = 20) and unselected cells was 1.7 (1.4-2.8) (n = 10). Comparing hemopoietic recovery between cycles of HDT supported by CD34-selected (n = 20) and unmanipulated cells (n = 10) there was a significant slowing with the CD34-selected cells; time to ANC > 1.0 = 13 days versus 10 days, platelets > 20 = 17 days versus 13 days, > 50 = 25 versus 17 days (all P values < 0.001). There was no correlation between the dose of CD34-selected cells infused and neutrophil/platelet recovery. DISCUSSION: We have demonstrated that, although unmanipulated PBPC achieve rapid hemopoietic recovery (at modest CD34 doses of < or = 2.8 x 10(6)/kg), CliniMACS-selected CD34+ cells (in the doses utilized in this study of < or = 2.6 x 10(6)/kg) result in significantly prolonged recovery.

Adult↗
PubMed2006

Complex multivariate sexual selection on male acoustic signaling in a wild population of Teleogryllus commodus.

Mate choice may impose both linear (i.e., directional) and nonlinear (i.e., quadratic and correlational) sexual selection on advertisement traits. Traditionally, mate recognition and sensory tuning have been thought to impose stabilizing (i.e., negative quadratic) sexual selection, whereas adaptive mate choice effects directional selection. It has been suggested that adaptive choice may exert positive quadratic and/or correlational sexual selection. Earlier, we showed that five structural components of the advertisement call of male field crickets (Teleogryllus commodus) were under multivariate stabilizing selection under laboratory conditions. Here we experimentally estimate selection on these five traits plus a measure of calling activity (the number of repeats in a looped bout of calling) in the field. There was general support for multivariate stabilizing selection on call structure, and calling activity was under strong positive directional selection, as predicted for a signal of genetic quality. There was, however, also appreciable correlational selection, suggesting an interaction between male call structure and calling effort. Interestingly, selection for short interbout durations of silence favored longer intercall durations in the field, in contrast to results from continuous looped call playback in the laboratory. We discuss the general importance of nonlinear selection in the honest signaling of genetic quality.

Acoustic Stimulation↗
PubMed2004

Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid.

Retinoids may be useful agents for the treatment of pancreatic cancer. However, retinoic acid receptor (RAR)-selective retinoids produce unwanted side effects. In contrast, retinoid X receptor (RXR)-selective retinoids produce fewer side effects; however, it was not known whether RXR-selective retinoids could reduce pancreatic tumor cell proliferation. In the present study, the novel RXR-selective retinoid, AGN194204, was compared with that of other retinoids for the ability to suppress pancreatic cancer cell proliferation. We treated various pancreatic cancer cell lines with receptor-selective ligands and cytotoxic agents and monitored the effects on cell proliferation, markers of apoptosis and cell cycle. Our results indicate that AGN194204, at concentrations >10 nM, inhibits proliferation of MIA PaCa-2 and BxPC-3 cells but not the proliferation of AsPC-1 cells. Moreover, in BxPC-3 and MIA PaCa-2 cells, AGN194204 was 10-100 times more effective than RAR-selective retinoids. AGN194204-dependent suppression of MIA PaCa-2 cell proliferation is associated with reduced cyclin E and cyclin-dependent kinase 6 (cdk6) level, but cyclin D1, cdk2 and cdk4 content is not altered. In addition, p27 level increases 2-fold. The RXR-selective antagonist, AGN195393, reverses the AGN194204-dependent growth inhibition and the decline in cyclin E and cdk6 levels. In contrast, these changes are not reversed by treatment with the RAR antagonist, AGN193109. AGN194204 did not appear to alter cell apoptosis as measured by change in cleavage of procaspase-3, -8 or -9. We also examined the effects AGN194204 co-treatment with cytotoxic agents. Treatment of MIA PaCa-2 cells with AGN194204 + cisplatin, gemcitabine, 5-fluorouracil, interferon (IFN)alpha or IFNgamma resulted in an additive but not synergistic reduction in MIA PaCa-2 cell number. These results indicate that AGN194204, an RXR-selective retinoid, is a more effective inhibitor of pancreatic cell proliferation than the RAR-selective retinoids, and further indicate that AGN194204 produces an additive reduction in cell number when given with other agents. Our results suggest that RXR-selective ligands, which are less toxic than RAR-selective ligands, may be suitable agents for the treatment of pancreatic cancer.

Antimetabolites, Antineoplastic↗
PubMed1997

Agonist peptide modulates T cell selection thresholds through qualitative and quantitative shifts in CD8 co-receptor expression.

Engagement of the TCR is a pivotal step in thymocyte development, ultimately resulting in the survival (positive selection) or loss (negative selection) of developing T cells. The roles of peptides and stromal cell interactions necessary for these selection events, however, are still poorly understood. To investigate the effects of agonist peptide in positive selection, we used a novel cell suspension model for in vitro thymic positive selection in adults. Target thymocytes from H-2Db-restricted TCR transgenic mice, specific to the lymphocytic choriomeningitis virus (LCMV) peptide bred on a non-selecting MHC background (H-2d or TAP-1-/-), were co-cultured with freshly isolated H-2b thymic stromal cells. In the presence of selecting stroma the nominal agonist LCMV peptide induced apoptosis at high concentrations and at low concentrations enhanced the efficiency of positive selection both in numbers of cells 'rescued' and kinetics of appearance of selected single-positive cells. We further illustrate down-modulation of CD8 alpha beta or CD8 beta at high but non-deleting concentrations of agonist peptide. This highlights the ability of the T cell, within the window of positive selection, to modify surface co-receptors both qualitatively and quantitatively in response to increasing avidity TCR-peptide-MHC interactions. The direct consequence of this would be to lower the total signaling events below the threshold for apoptosis induction. Hence if self peptide were not presented in sufficient quantities in the thymus, autoreactive cells may escape deletion and may actually be positively selected.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Sex selection may be inadvertently performed in in-vitro fertilization-embryo transfer programmes.

The present study aims to ascertain whether sex selection may be inadvertently performed in human in-vitro fertilization (IVF) and embryo transfer (IVF-embryo transfer) programmes when selecting for high quality embryos (those with the fastest cleaving rates and/or the best morphology) at the fresh transfer cycle. All patients entering into the study were treated with gonadotrophins after pituitary suppression with gonadotrophin-releasing hormone agonists (GnRHa) and had intrauterine embryo transfer on day 2 post-insemination. These patients were retrospectively divided into three groups according to whether the difference in mean number of cells between embryos transferred and all embryos available for transfer in a given cycle was less than (negative selection), equal to (no selection) or greater (positive selection) than zero. In cycles resulting in singleton births, the sex ratio of the resulting babies was significantly (P < or = 0.005) shifted toward the female (88.8%) and to the male (90.0%) in the negative and positive selection groups respectively. No shift in sex ratio was observed in cycles resulting in multiple births. Maternal age was another independent factor affecting sex ratio at birth. Sex ratio was significantly (P < or = 0.05) skewed in favour of males (62.7%) and females (71.4%) in women < 35 and > or = 35 years of age respectively. Maternal age, number of embryos transferred and the event of selecting or not selecting the slowest cleaving embryos for transfer were entered automatically in a three-group discriminant model for distinguishing cycles resulting in only boys, both boys and girls, and only girls. These data suggest that (i) sex selection may be inadvertently performed in IVF-embryo transfer programmes when selecting for high quality embryos at the fresh transfer cycles; (ii) human endometria may be favourable, indifferent or hostile to either fast cleaving or slow cleaving embryos depending on maternal age; and (iii) "natural' sex selection may be performed for social, psychological or medical reasons.

Adult↗
PubMed1999

Analysis of MHC class II and class IV restriction fragment length polymorphism in chicken lines divergently selected for multitrait immune response.

In the present study, chickens of four lines divergently selected for high (H) and low (L) immunocompetence in replicate were analyzed to investigate polymorphisms of MHC class II and MHC class IV on the molecular level associated with selection. The long-term selection experiment for multitrait immunocompetence was carried out in replicates and allows, therefore, the opportunity to distinguish effects of selection from other genetic factors. The SacI-digested DNA was hybridized individually with MHC class II and MHC class IV gene probes. The MHC class II RFLP analysis revealed four polymorphic bands and only one of them showed a significant difference between the selection directions H and L pooled between replicates. The small frequency differences of this band relative to the long-term selection suggest that this MHC class II fragment may contain genetic elements that are only slightly associated with the immune response traits used for selection. The hybridization with the MHC class IV probe displayed 26 scorable bands, of which 18 were polymorphic. In most instances, the differences between the lines were likely caused by the influence of genetic factors other than selection for multitrait immunocompetence. Only one band displayed a consistency in difference between selection directions in both replicates and no frequency difference between replicates. This band was almost completely absent in both H sublines, but at a frequency of about 50% in both L sublines. The general results of this study did not reveal major differences in band frequencies that indicate a close association of MHC class II and MHC class IV polymorphic markers to the divergent selection for multitrait immune response. Although the MHC makes a crucial contribution in immune response, it may have been difficult to detect single-gene associations with the selection criteria of this study, because of the myriad of components contributing to general immune responses measured in vivo.

Animals↗
PubMed2002

Sexual selection and speciation in mammals, butterflies and spiders.

Recently refined evolutionary theories propose that sexual selection and reproductive conflict could be drivers of speciation. Male and female reproductive optima invariably differ because the potential reproductive rate of males almost always exceeds that of females: females are selected to maximize mate 'quality', while males can increase fitness through mate 'quantity'. A dynamic, sexually selected conflict therefore exists in which 'competitive' males are selected to override the preference tactics evolved by 'choosy' females. The wide variation across taxa in mating systems therefore generates variance in the outcome of intrasexual conflict and the strength of sexual selection: monandry constrains reproductive heterozygosity and allows female choice to select and maintain particular (preferred) genes; polyandry promotes reproductive heterozygosity and will more likely override female choice. Two different theories predict how sexual selection might influence speciation. Traditional ideas indicate that increased sexual selection (and hence conflict) generates a greater diversity of male reproductive strategies to be counteracted by female mate preferences, thus providing elevated potentials for speciation as more evolutionary avenues of male-female interaction are created. A less intuitively obvious theory proposes that increased sexual selection and conflict constrains speciation by reducing the opportunities for female mate choice under polyandry. We use a comparative approach to test these theories by investigating whether two general measures of sexual selection and the potential for sexual conflict have influenced speciation. Sexual size dimorphism (across 480 mammalian genera, 105 butterfly genera and 148 spider genera) and degree of polyandry (measured as relative testes size in mammals (72 genera) and mating frequency in female butterflies (54 genera)) showed no associations with the variance in speciosity. Our results therefore show that speciation occurs independently of sexual selection.

Animals↗
PubMed2006

Application of random effects to the study of resource selection by animals.

1. Resource selection estimated by logistic regression is used increasingly in studies to identify critical resources for animal populations and to predict species occurrence. 2. Most frequently, individual animals are monitored and pooled to estimate population-level effects without regard to group or individual-level variation. Pooling assumes that both observations and their errors are independent, and resource selection is constant given individual variation in resource availability. 3. Although researchers have identified ways to minimize autocorrelation, variation between individuals caused by differences in selection or available resources, including functional responses in resource selection, have not been well addressed. 4. Here we review random-effects models and their application to resource selection modelling to overcome these common limitations. We present a simple case study of an analysis of resource selection by grizzly bears in the foothills of the Canadian Rocky Mountains with and without random effects. 5. Both categorical and continuous variables in the grizzly bear model differed in interpretation, both in statistical significance and coefficient sign, depending on how a random effect was included. We used a simulation approach to clarify the application of random effects under three common situations for telemetry studies: (a) discrepancies in sample sizes among individuals; (b) differences among individuals in selection where availability is constant; and (c) differences in availability with and without a functional response in resource selection. 6. We found that random intercepts accounted for unbalanced sample designs, and models with random intercepts and coefficients improved model fit given the variation in selection among individuals and functional responses in selection. Our empirical example and simulations demonstrate how including random effects in resource selection models can aid interpretation and address difficult assumptions limiting their generality. This approach will allow researchers to appropriately estimate marginal (population) and conditional (individual) responses, and account for complex grouping, unbalanced sample designs and autocorrelation.

Animals↗
PubMed1992

Selective attention in auditory processing as reflected by event-related brain potentials.

Measures of event-related brain potentials (ERPs) have revealed two kinds of selective-attention mechanisms that operate on attended and unattended auditory stimuli. The processing negativity of the ERP reveals a mechanism of intramodal selective attention in the auditory cortex controlled by the frontal cortex. This mechanism selects attended auditory stimuli for further processing when they differ from unattended stimuli in location or tonal frequency. Studies of intermodal selective attention have compared auditory ERPs during auditory and visual attention. At least in part different brain mechanisms may be involved in the selection of auditory stimuli among other auditory stimuli (intramodal selective attention) and in the selection of auditory stimuli among visual stimuli (intermodal selective attention). This is suggested by the results showing that the earlier component of the processing negativity, which is generated in the auditory cortex during intramodal selective attention, differs in scalp distribution from the early attention-related negativity elicited during intermodal selective attention. With respect to the unattended auditory stimuli, ERP studies of selective attention suggest that physical features of these stimuli are extensively processed. This is shown by the mismatch negativity component of the ERP, which is usually elicited by infrequent physical deviations in an auditory stimulus sequence both when this sequence is attended and when it is ignored. This would be impossible if the physical stimulus features were not extensively processed, even in the absence of attention.

Arousal↗
PubMedDate not supplied

Unexpected effects of prey dimensions and morphologies on the size selective feeding by two bacterivorous flagellates (Ochromonas sp. and Spumella sp.).

Current models on protistan size-selective feeding assume that contact probability is the factor that largely explains observed food preferences. Contact probability is generally expected to be positively correlated with prey size and therefore to explain observed food selection for larger prey items. We critically tested these basic assumptions on size-selective feeding using the interception-feeding chrysomonad nanoflagellates Ochromonas sp. and Spumella sp. Mechanisms of differential feeding were studied during distinct stages of the selection process (i.e. contact probability, capture efficiency, ingestion efficiency, and differential digestion) by means of high-resolution video microscopy. Food selection was investigated using a mixture of microspheres ranging from 0.3-2.2 microm in diam., as well as a mixed bacterial community. In contrast to current model assumptions, the contact probability was highest for microspheres of intermediate size (0.9-1.2 microm), but was not generally positively correlated with prey size over the whole prey size range. Capture and ingestion also proved to be involved in size selection: these patterns were also independent of the food concentration (p = 0.968 for Ochromonas, p = 0.971 for Spumella). Even though the capture rate was significantly higher for attached flagellates than for swimming flagellates (p < 0.001), size selectivity was not affected (p > 0.05). Our results indicate that: (i) size selection is not actively regulated by these flagellates, but is a passive process; (ii) contact probability is not generally positively correlated with prey size, but shows a maximum for intermediate-sized prey in the prey size spectrum of 0.3-2.2 microm; and (iii) selection steps other than contact probability are crucial for size selection and should be integrated in models on size selection.

Animals↗
PubMed2007

Differential selection of acridine resistance mutations in human DNA topoisomerase IIbeta is dependent on the acridine structure.

Type II DNA topoisomerases are targets of acridine drugs. Nine mutations conferring resistance to acridines were obtained by forced molecular evolution, using methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA), methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA), methyl N-(4'-(9-acridinylamino)-phenyl) carbamate hydrochloride (AMCA), and N-[2-(dimethylamino)ethyl]acridines-4-carboxamide (DACA) as selection agents. Mutations betaH514Y, betaE522K, betaG550R, betaA596T, betaY606C, betaR651C, and betaD661N were in the B' domain, and betaG465D and betaP732L were not. With AMCA, four mutations were selected (betaE522K, betaG550R, betaA596T, and betaD661N). Two mutations were selected with mAMCA (betaY606C and betaR651C) and two with mAMSA (betaG465D and betaP732L). It is interesting that there was no overlap between mutation selection with AMCA and mAMSA or mAMCA. AMCA lacks the methoxy substituent present in mAMCA and mAMSA, suggesting that this motif determines the mutations selected. With the fourth acridine DACA, five mutations were selected for resistance (betaG465D, betaH514Y, betaG550R, betaA596T, and betaD661N). betaG465D was selected with both DACA and mAMSA, and betaG550R, betaA596T, and betaD661N were selected with both DACA and AMCA. DACA lacks the anilino motif of the other three drugs but retains the acridine ring motif. The overlap in selection with DACA and mAMSA or AMCA suggests that altered recognition of the acridine moiety may be involved in these mutations. We used restriction fragment length polymorphisms and heteroduplex analysis to demonstrate that some mutations were selected multiple times (betaG465D, betaE522K, betaG550R, betaA596T, and betaD661N), whereas others were selected only once (betaH514Y, betaY606C, betaR651C, and betaP732L). Here, we compare the drug resistance profile of all nine mutations and report the biochemical characterization of three, betaG550R, betaY606C, and betaD661N.

Acridines↗
PubMed2002

Selective plasma filtration for treatment of fulminant hepatic failure induced by D-galactosamine in a pig model.

BACKGROUND: Plasma exchange may be useful for treating patients with fulminant hepatic failure but during the procedure growth factors that are important for hepatic regeneration are discarded. Addition of a selective plasma filter to the plasmapheresis circuit could eliminate protein bound toxic substances and retain growth factors for hepatic regeneration. This process is called selective plasma filtration. AIMS: To determine if selective plasma filtration could be a useful treatment modality for fulminant hepatic failure. METHODS: The system was tested in five groups of pigs with fulminant hepatic failure induced by galactosamine: group I, diseased control group (n=5); group II, sham control, (n=6); group III, plasma exchange (n=6); group IV, treatment with AC-1770 selective plasma filter (n=7); and group V, treatment with AC-1730 selective plasma filter which had a smaller pore size than AC-1770 (n=7). Fresh pig plasma was given to replace filtered plasma in pigs of groups III, IV, and V. Treatment was initiated 48 hours after administration of 0.75 g/kg galactosamine. The efficacy of selective plasma filtration was assessed by survival rate and improvement in haematological, biochemical, and immunohistological parameters. RESULTS: Pigs treated with AC-1770 or AC-1730 selective plasma filters survived longer than the other groups (group I: 55 (10) hours; group II: 68 (7) hours; group III: 91 (10) hours; group IV: 269 (156) hours; group V: 950 (555) hours). One pig in group IV survived for 50 days; one pig in group V survived for 77 days and another pig in group V is still alive (>150 days). After treatment, plasma levels of aspartate aminotransferase, bilirubin, bile acid, ammonia, lactate dehydrogenase, and alpha-glutathione-S-transferase decreased. Substantial amounts of tumour necrosis factor alpha (TNF-alpha) and endotoxin were found in the filtrate. The selective plasma filtration groups retained significantly higher amounts of hepatocyte growth factor than plasma exchange alone. Similar TNF-alpha clearance was observed in the selective plasma filtration groups and the plasma exchange group. On day 4, significant improvement in liver function, as measured by the indocyanine green clearance test, was observed in groups IV and V but not in the other groups. A higher regeneration index of hepatocytes was also observed in the groups treated with AC-1770 and AC-1730 selective plasma filters. CONCLUSION: Selective plasma filtration improved survival time and expedited liver regeneration in pigs with fulminant hepatic failure.

Animals↗
PubMed1990

Selectivity of cat area 18 neurons for direction and speed in depth.

1. Fifty-eight area 18 cells recorded in anesthetized and paralyzed cats were tested for selectivity for direction in depth after their monocular velocity characteristics and static disparity profile were determined. 2. Direction in depth was produced by changing the speed and direction in the two eyes, but keeping the speed along axes in depth constant. 3. Forty-two cells were completely investigated, which means that direction in depth selectivity was tested at least at two different position disparities and two different bar speeds. Seven out of the 42 cells were accepted as direction in depth selective. 4. The 16 remaining cells were incompletely tested. Only one of them was direction in depth selective at the disparity and speed tested and shared all the properties of the seven completely tested direction in depth selective cells. Therefore we estimated that 8/58, i.e., 14% of the area 18 cells are direction in depth selective. 5. The direction in depth selective cells are a very homogeneous class: they all belong to the S family, are velocity tuned, monocular, prefer orientations close to vertical, and have a broad inhibitory or an unmodulated position disparity profile. 6. Direction in depth selectivity arises both from monocular properties and binocular interactions. These binocular interaction profiles can be symmetric or asymmetric. The change of these interaction profiles with changes in base speed can be summarized as changes in level of inhibition for the axes corresponding to equal speed in the two eyes on one hand and changes in the slope of the inhibition gradient centered on these axes of equal speed on the other hand. 7. Nineteen of the 58 cells were tested for selectivity for speed along trajectories in depth. All five direction in depth selective cells tested were also tuned to speed in depth. This suggests that area 18 contributes to the elaboration of a 3D velocity map. 8. A wiring diagram that accounts for the binocular interactions underlying direction selectivity in depth is presented.

Animals↗