Automated clustering workflows are increasingly used for the analysis of high parameter flow cyto... more Automated clustering workflows are increasingly used for the analysis of high parameter flow cytometry data. This trend calls for algorithms which are able to quickly process tens of millions of data points, to compare results across subjects or time points, and to provide easily actionable interpretations of the results. To this end, we created Tailor, a model‐based clustering algorithm specialized for flow cytometry data. Our approach leverages a phenotype‐aware binning scheme to provide a coarse model of the data, which is then refined using a multivariate Gaussian mixture model. We benchmark Tailor using a simulation study and two flow cytometry data sets, and show that the results are robust to moderate departures from normality and inter‐sample variation. Moreover, Tailor provides automated, non‐overlapping annotations of its clusters, which facilitates interpretation of results and downstream analysis. Tailor is released as an R package, and the source code is publicly availa...
Antibody-staining methods and computer-aided microscopic systems have been used to generate high-... more Antibody-staining methods and computer-aided microscopic systems have been used to generate high-resolution panoramic maps of specific neuronal populations in the human brain (4,6,11). This report focuses on the problems inherent in attempting high-resolution mapping of large brain sections, and describes how they are solved by computer-aided mapping. Further applications of computers to the study of brain structure are considered.
1. Accumulated evidence from the literature led us to investigate whether centrally generated act... more 1. Accumulated evidence from the literature led us to investigate whether centrally generated activity was present within a central neuronal network for cardiovascular control. An in vitro approach using a brain stem slice preparation was employed to study the cardiorespiratory region of the nucleus of the solitary tract (NTS) in the rat. 2. We have discovered rhythmically active neurons within a restricted part of the cardiorespiratory NTS. These neurons were localized to regions directly medial and dorsomedial to the solitary tract (ts) at levels 0.2 mm rostral to obex extending caudally to the rostral part of the commissural subnucleus, an area considered to be concerned with cardiovascular regulation. Although other subnuclei were explored for neurons with ongoing activity (i.e., dorsolateral, dorsal, and interstitial) at levels 1.5 mm caudal to 0.75 mm rostral to obex, we failed to find similarly tonically active cells. 3. Intra- or extracellular recordings were made from 85 neurons with a mean firing rate of 5.1 +/- 0.3 (SE) Hz (range 1-15). The majority of these (n = 75) received an excitatory synaptic input from the ipsilateral ts, with latencies ranging between 4 and 20 ms. 4. To determine whether the tonically rhythmic cells were dependent on synaptic excitatory drives or were inherent to the cell, we tested, in 45 neurons recorded extracellularly, the effect of blocking synaptic inputs mediated by excitatory amino acids by applying either DL-2-amino-5-phosphonovaleric acid [APV; N-methyl-D-aspartate (NMDA) antagonist] or MK-801 (NMDA antagonist) with kynurenic acid (Kyn; NMDA, quisqualate, and kainate receptor blocker) to the bath. After bath application of APV and Kyn or MK-801 and Kyn, two different responses were observed. In 19 cells ongoing rhythmic activity was unperturbed, but firing was completely silenced in 26 neurons. In all cases neurons failed to respond to glutamate delivered locally, and the synaptic input evoked from the ts was blocked. This evidence indicates the existence of two cell types: autoactive (AA) or pacemaker-like neurons, the discharge pattern of which depends on intrinsic properties, and synaptically driven (SD) neurons, the activity of which is driven by synaptic inputs. 5. Cobalt chloride (Co) was used to block synaptic effects and was found to increase the discharge rate of AA neurons by 9.9 Hz on average (i.e., cells resistant to APV and Kyn or MK-801 and Kyn). However, the rhythmic activity of cells previously silenced with excitatory amino acid antagonists (i.e., SD cells) was also abolished in the presence of Co.(ABSTRACT TRUNCATED AT 400 WORDS)
Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditiona... more Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes. Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V, CD3, CD31, CD41a, CD64, CD105, and CD144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet-free plasma was separated from whole blood by one-step centrifugation for microparticle analysis. Microparticles ...
Electron-impact ionization of Zn + and Ga +. Wade T. Rogers * , G. Stefani , R. Camilloni , a... more Electron-impact ionization of Zn + and Ga +. Wade T. Rogers * , G. Stefani , R. Camilloni , and Gordon H. Dunn Joint Institute for Laboratory Astrophysics, University of Colorado and National Bureau of Standards, Boulder, Colorado 80309. ...
Crossed beams of electrons and Li + ions have been used to measure the absolute emission cross se... more Crossed beams of electrons and Li + ions have been used to measure the absolute emission cross section for the process, e+Li + (1 1 S)→e+Li + (n 3 l)→hν (548.5 nm), from below the threshold at 61.26 to 162 eV. The cross section exhibits the sharp onset at threshold characteristic ...
1990 IJCNN International Joint Conference on Neural Networks, 1990
This research is based on the premise that computational principles evolved by biological systems... more This research is based on the premise that computational principles evolved by biological systems are applicable to engineering devices, that an interaction of ongoing neurobiological experiments with computer simulation will be productive in extracting computational principles, and that tools for the analysis of neurobiological systems and for their modeling and simulation have evolved to the point where success is probable. The approach is based on neuroanatomical experiments to establish the connectional circuit. However, it is found that knowledge of network architecture (connectivity) is not enough. The biophysics of neurons leads to important diversity of intrinsic properties among constituents of a network. Consequently, neurons have dynamical response properties that can sensitively affect, or even completely alter, the functioning of a distributed network. Experimentally determined facts of both connection and biophysics must inform computational models in order to capture network dynamics/performance. Simulation results in turn generate hypotheses which drive further testing in biological experiments
IJCNN-91-Seattle International Joint Conference on Neural Networks, 1991
The authors present a model of the neuronal network that performs adaptive control of the vertebr... more The authors present a model of the neuronal network that performs adaptive control of the vertebrate cardiovascular system. The model incorporates new data on the cell groups and connections of the circuit, on the synaptic activity and discharge properties of cardiovascular neurons in the brainstem, and on the modulation of their excitability by nonsynaptic intrinsic membrane properties. Some of these data have been represented in a computational model, thus allowing simulations to generate hypotheses regarding design principles of the control system
Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular f... more Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.
To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define th... more To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine. Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function. Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders. Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.
Automated clustering workflows are increasingly used for the analysis of high parameter flow cyto... more Automated clustering workflows are increasingly used for the analysis of high parameter flow cytometry data. This trend calls for algorithms which are able to quickly process tens of millions of data points, to compare results across subjects or time points, and to provide easily actionable interpretations of the results. To this end, we created Tailor, a model‐based clustering algorithm specialized for flow cytometry data. Our approach leverages a phenotype‐aware binning scheme to provide a coarse model of the data, which is then refined using a multivariate Gaussian mixture model. We benchmark Tailor using a simulation study and two flow cytometry data sets, and show that the results are robust to moderate departures from normality and inter‐sample variation. Moreover, Tailor provides automated, non‐overlapping annotations of its clusters, which facilitates interpretation of results and downstream analysis. Tailor is released as an R package, and the source code is publicly availa...
Antibody-staining methods and computer-aided microscopic systems have been used to generate high-... more Antibody-staining methods and computer-aided microscopic systems have been used to generate high-resolution panoramic maps of specific neuronal populations in the human brain (4,6,11). This report focuses on the problems inherent in attempting high-resolution mapping of large brain sections, and describes how they are solved by computer-aided mapping. Further applications of computers to the study of brain structure are considered.
1. Accumulated evidence from the literature led us to investigate whether centrally generated act... more 1. Accumulated evidence from the literature led us to investigate whether centrally generated activity was present within a central neuronal network for cardiovascular control. An in vitro approach using a brain stem slice preparation was employed to study the cardiorespiratory region of the nucleus of the solitary tract (NTS) in the rat. 2. We have discovered rhythmically active neurons within a restricted part of the cardiorespiratory NTS. These neurons were localized to regions directly medial and dorsomedial to the solitary tract (ts) at levels 0.2 mm rostral to obex extending caudally to the rostral part of the commissural subnucleus, an area considered to be concerned with cardiovascular regulation. Although other subnuclei were explored for neurons with ongoing activity (i.e., dorsolateral, dorsal, and interstitial) at levels 1.5 mm caudal to 0.75 mm rostral to obex, we failed to find similarly tonically active cells. 3. Intra- or extracellular recordings were made from 85 neurons with a mean firing rate of 5.1 +/- 0.3 (SE) Hz (range 1-15). The majority of these (n = 75) received an excitatory synaptic input from the ipsilateral ts, with latencies ranging between 4 and 20 ms. 4. To determine whether the tonically rhythmic cells were dependent on synaptic excitatory drives or were inherent to the cell, we tested, in 45 neurons recorded extracellularly, the effect of blocking synaptic inputs mediated by excitatory amino acids by applying either DL-2-amino-5-phosphonovaleric acid [APV; N-methyl-D-aspartate (NMDA) antagonist] or MK-801 (NMDA antagonist) with kynurenic acid (Kyn; NMDA, quisqualate, and kainate receptor blocker) to the bath. After bath application of APV and Kyn or MK-801 and Kyn, two different responses were observed. In 19 cells ongoing rhythmic activity was unperturbed, but firing was completely silenced in 26 neurons. In all cases neurons failed to respond to glutamate delivered locally, and the synaptic input evoked from the ts was blocked. This evidence indicates the existence of two cell types: autoactive (AA) or pacemaker-like neurons, the discharge pattern of which depends on intrinsic properties, and synaptically driven (SD) neurons, the activity of which is driven by synaptic inputs. 5. Cobalt chloride (Co) was used to block synaptic effects and was found to increase the discharge rate of AA neurons by 9.9 Hz on average (i.e., cells resistant to APV and Kyn or MK-801 and Kyn). However, the rhythmic activity of cells previously silenced with excitatory amino acid antagonists (i.e., SD cells) was also abolished in the presence of Co.(ABSTRACT TRUNCATED AT 400 WORDS)
Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditiona... more Psoriasis, especially when severe, is a risk factor for cardiometabolic disease beyond traditional risk factors. The mechanism of atherogenesis in psoriasis remains unknown. Cell membrane vesicles (ie, microparticles), released upon cell activation or apoptosis, have recently been associated with cardiometabolic disease and may play a pathogenic role. Microparticle levels, particularly from endothelial cells and platelets, are elevated in patients with cardiovascular disorders, metabolic syndrome, other inflammatory diseases, autoimmune conditions, and have been shown to be predictive of cardiovascular outcomes. Concentrations of microparticles with positive expression for any of 7 cell surface markers (Annexin V, CD3, CD31, CD41a, CD64, CD105, and CD144) were measured in blood samples from psoriasis patients (n=53) and control subjects without psoriasis (n=41). Platelet-free plasma was separated from whole blood by one-step centrifugation for microparticle analysis. Microparticles ...
Electron-impact ionization of Zn + and Ga +. Wade T. Rogers * , G. Stefani , R. Camilloni , a... more Electron-impact ionization of Zn + and Ga +. Wade T. Rogers * , G. Stefani , R. Camilloni , and Gordon H. Dunn Joint Institute for Laboratory Astrophysics, University of Colorado and National Bureau of Standards, Boulder, Colorado 80309. ...
Crossed beams of electrons and Li + ions have been used to measure the absolute emission cross se... more Crossed beams of electrons and Li + ions have been used to measure the absolute emission cross section for the process, e+Li + (1 1 S)→e+Li + (n 3 l)→hν (548.5 nm), from below the threshold at 61.26 to 162 eV. The cross section exhibits the sharp onset at threshold characteristic ...
1990 IJCNN International Joint Conference on Neural Networks, 1990
This research is based on the premise that computational principles evolved by biological systems... more This research is based on the premise that computational principles evolved by biological systems are applicable to engineering devices, that an interaction of ongoing neurobiological experiments with computer simulation will be productive in extracting computational principles, and that tools for the analysis of neurobiological systems and for their modeling and simulation have evolved to the point where success is probable. The approach is based on neuroanatomical experiments to establish the connectional circuit. However, it is found that knowledge of network architecture (connectivity) is not enough. The biophysics of neurons leads to important diversity of intrinsic properties among constituents of a network. Consequently, neurons have dynamical response properties that can sensitively affect, or even completely alter, the functioning of a distributed network. Experimentally determined facts of both connection and biophysics must inform computational models in order to capture network dynamics/performance. Simulation results in turn generate hypotheses which drive further testing in biological experiments
IJCNN-91-Seattle International Joint Conference on Neural Networks, 1991
The authors present a model of the neuronal network that performs adaptive control of the vertebr... more The authors present a model of the neuronal network that performs adaptive control of the vertebrate cardiovascular system. The model incorporates new data on the cell groups and connections of the circuit, on the synaptic activity and discharge properties of cardiovascular neurons in the brainstem, and on the modulation of their excitability by nonsynaptic intrinsic membrane properties. Some of these data have been represented in a computational model, thus allowing simulations to generate hypotheses regarding design principles of the control system
Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular f... more Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.
To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define th... more To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine. Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function. Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders. Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.
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