David X: economics and medical ethics.
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Economics, Medical↗
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QTL for pubertal and seasonality traits in male Père David's x red deer interspecies hybrids.
The unique Pere David's (Elaphurus davidianus) x red deer (Cervus elaphus) backcross hybrid has been used to search for evidence of quantitative trait loci (QTL) for antler pubertal (date and live weight at pedicle initiation) and antler seasonality (date of antler cleaning and casting) traits in temperate species of deer. Analyses using marker information revealed evidence for a QTL for date at pedicle initiation (LOD = 3.7) and live weight at pedicle initiation (LOD = 3.1). These QTL explained 13% and 11% of the phenotypic variance in these traits, respectively.
Animals↗
Genetic analysis of Père David's x red deer interspecies hybrids.
Interspecies hybrids provide unique opportunities for fundamental genetic analyses and for genetic improvement of farmed deer. We have bred F1 hybrids by artificial insemination of red deer hinds (Cervus elaphus) with semen from Père David's deer (Elaphurus davidianus). The male and female F1 Père David deer x red deer hybrids were fertile and in matings with red deer have produced over 300 viable backcross hybrids. DNA was collected from the backcross progeny as an international reference panel for gene linkage mapping and to investigate associations between segregating species-specific genetic markers and phenotypic traits. We have measured a range of phenotypic traits in the backcross hybrids and red deer. Several traits appear suitable for genetic analysis using mapped genetic markers, including gestation length, growth rate, live weight, head morphometrics, and tail length. Typically these traits show a large difference between Père David's deer and red deer and a high variance in the backcross so that many individuals have a phenotype outside the range observed in red deer.
Animals↗
QTL for live weight traits in Père David's x red deer interspecies hybrids.
Interspecies hybrids between Père David's deer (Elaphurus davidianus) and red deer (Cervus elaphus) have proved to be a powerful resource in the search for quantitative trait loci (QTL) in deer. Several regions of the genome with significant effects on live weight and growth rates in backcross hybrids were detected. These include putative QTL for 6-month live weight (LOD 3.90) on linkage group 12, for 14-month live weight (LOD 3.19) on linkage group 1, three putative QTL for growth rate from 3 to 6 months (LOD 4.19 on linkage group 12, LOD 3.92 on linkage group 12, and LOD 3.34 on linkage group 5). In addition, linkage groups 20 and 1 appear to be associated with live weight traits between 9 and 16 months. The variance in traits explained by these QTL ranged between 5.3% and 11.2%. Allele substitution with Père David's alleles at different loci had both positive and negative effects on live weights and growth rates.
Animals↗
Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.
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Adult↗
Cell-type signatures of Alzheimer's disease shared across population groups.
Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease1-9, but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB+ and CD74+ subgroups), astrocytic (SERPINH1+, CD44+ and WIF1+ subgroups) and neuronal (SST+ GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.
Female↗
Letter: Some comments on "myelin membrane structure as revealed by x-ray diffraction" by David Harker.
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Cell Membrane↗
Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
Amino Acid Sequence↗
Reply to "myelin membrane structure as revealed by x-ray diffraction" by David Harker.
The interpretation of the heavy metal-labeled data can either be accomplished with the analysis of the observed intensity differences (Akers and Parsons) or with the analysis of the observed structure amplitude changes (Harker). Both methods of analysis give essentially the same results: that two possible electron density distributions are valid, within experimental error, depending on whether there are one or two metal-labeling sites within the membrane. At present, the correct choice must rest on either the introduction of additional physical and chemical data on the position of the proteins and lipids or on an independent phasing technique such as the Hosemann-Bagchi Q-function.
Animals↗
Release and elimination of soluble vasoactive factors during percutaneous coronary intervention of saphenous vein grafts: analysis using the PercuSurge GuardWire distal protection device.
BACKGROUND: The presence of no-reflow substantially increases the risk of major adverse clinical events (MACE) in percutaneous coronary artery interventions (PCI). Distal protection devices may eliminate both debris and soluble factors that can lead to no-reflow. This study was designed to evaluate the soluble factors released and eliminated by the PercuSurge GuardWire during SVG intervention. METHODS: Twenty-eight consecutive patients underwent PCI on 34 lesions in 31 SVGs using the PercuSurge GuardWire. Blood was taken prior to PCI for baseline measurement of: (1) vasoconstrictive factors: endothelin (ET) and serotonin (5-HT); (2) thrombotic factors: tissue factor (TF), plasminogen activator inhibitor (PAI-1), thrombin/antithrombin III complex (TAT), and prothrombin fragment F1+2 (F1+2); and (3) inflammatory factors: soluble CD40 ligand (sCD40L) and soluble E-selectin. After stenting and before deflating the distal protection balloon, 2 aspiration runs were performed with the PercuSurge Export Catheter and sent for analysis. RESULTS: Clinical follow-up was conducted at an average of 6 +/- 3 months. SVG PCI resulted in a substantial increase in levels of vasoconstrictive factors, including ET (3 x increase; p < 0.001) and 5-HT (9.7 x increase; p = 0.031); thrombotic factors, including TF (4.5 x increase; p = 0.005), TAT (2.4 x increase; p < 0.001), and F1+2 (2.4 x increase; p < 0.001). Pro-inflammatory factors were also released during the procedure. Levels of sCD40L and soluble E-selectin increased 123% (p = 0.003) and 25% (p < 0.001), respectively. CONCLUSIONS: SVG PCI results in an immediate increase in vasoactive factors, including vasoconstrictive, thrombotic and inflammatory factors. The PercuSurge GuardWire effectively removes these soluble factors, which may account for reduction of no-reflow and other complications during SVG interventions.
Aged↗
Angiotensin II dilates bovine adrenal cortical arterioles: role of endothelial nitric oxide.
Adrenal steroidogenesis is modulated by humoral and neuronal factors and blood flow. Angiotensin II (AII) stimulates adrenal cortical aldosterone and cortisol production and medullary catecholamine release. However, AII regulation of adrenal vascular tone has not been characterized. We examined the effect of AII on diameters of cannulated bovine adrenal cortical arteries. Cortical arteries (average internal diameter = 230 microm) were constricted with U46619 and concentration-diameter responses to AII (10(-13) to 10(-8) mol/liter) were measured. In endothelium-intact arteries, AII induced dilations at low concentrations (maximum dilation = 25 +/- 6% at 10(-10) mol/liter) and constrictions at high concentrations (maximum constriction = 25 +/- 18% at 10(-8) mol/liter). AII constrictions were blocked by the angiotensin type 1 (AT1) receptor antagonist, losartan (10(-6) mol/liter). AII dilations were enhanced by losartan (maximal dilation = 48 +/- 8%), abolished by endothelial cell removal or N-nitro-L-arginine (L-NA, 3 x 10(-5) mol/liter) and inhibited by the angiotensin type 2 (AT2) receptor antagonist, PD123319 (10(-6) mol/liter, maximal dilation = 18 +/- 4%). In a 4,5-diaminofluorescein diacetate nitric oxide (NO) assay of isolated cortical arteries, AII stimulated NO production, which was abolished by PD123319, L-NA, or endothelial cell removal. Western immunoblot of arterial homogenates and endothelial and zona glomerulosa cell lysates revealed 48-kD and 50-kD bands corresponding to AT1 and AT2 receptors, respectively, in all three and a 140-kD band corresponding to endothelial NO synthase in endothelial cells and arteries. Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Purification and molecular cloning of porcine intestinal glycerol-ester hydrolase--evidence for its identity with carboxylesterase.
A glycerol-ester hydrolase was purified to homogeneity from porcine intestinal mucosa using a partial delipidation method and an eight-step purification procedure. The isolation scheme used gave a 483-fold purification, resulting in a pure enzyme with a specific activity on tributyrin of 290 micromol x min(-1) x mg(-1). The molecular mass of the enzyme was estimated at 240 kDa, based on the results of size-exclusion chromatography, and at 60 kDa, as determined by SDS/PAGE analysis. The isoelectric focusing data obtained indicated that only one isoform with a pI of 5.1 was present. Complete identity was found to exist between the N-terminal sequence of the first 25 amino acid residues and that of a porcine liver carboxylesterase. A full-length cDNA coding for the enzyme was isolated from pig small intestine. We observed that the corresponding protein originally named intestinal glycerol-ester hydrolase definitely belongs to the carboxylesterase family. The deduced amino acid sequence consisted of 565 residues and showed 97% identity with that of porcine liver carboxylesterase and more than 50% identity with those of other carboxylesterases from different mammalian species.
Amino Acid Sequence↗
Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries.
Adrenal steroidogenesis is closely correlated with increases in adrenal blood flow. Many reports have studied the regulation of adrenal blood flow in vivo and in perfused glands, but until recently few studies have been conducted on isolated adrenal arteries. The present study examined vasomotor responses of isolated bovine small adrenal cortical arteries to histamine, an endogenous vasoactive compound, and its mechanism of action. In U-46619-precontracted arteries, histamine (10(-9)-5 x 10(-6) M) elicited concentration-dependent relaxations. The relaxations were blocked by the H(1) receptor antagonists diphenhydramine (10 microM) or mepyramine (1 microM) (maximal relaxations of 18 +/- 6 and 22 +/- 6%, respectively, vs. 55 +/- 5% of control) but only partially inhibited by the H(2) receptor antagonist cimetidine (10 microM) and the H(3) receptor antagonist thioperamide (1 microM). Histamine-induced relaxations were also blocked by the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA, 30 microM; maximal relaxation of 13 +/- 7%) and eliminated by endothelial removal or L-NA combined with the cyclooxgenase inhibitor indomethacin (10 microM). In the presence of adrenal zona glomerulosa (ZG) cells, histamine did not induce further relaxations compared with histamine alone. Histamine (10(-7)-10(-5) M) concentration-dependently increased aldosterone production by adrenal ZG cells. Compound 48/80 (10 microg/ml), a mast cell degranulator, induced significant relaxations (93 +/- 0.6%), which were blocked by L-NA plus indomethacin or endothelium removal, partially inhibited by the combination of the H(1), H(2), and H(3) receptor antagonists, but not affected by the mast cell stabilizer sodium cromoglycate (1 mM). These results demonstrate that histamine causes direct relaxation of small adrenal cortical arteries, which is largely mediated by endothelial NO and prostaglandins via H(1) receptors. The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation.
Adrenal Cortex↗
Calcium-induced calcium release and cyclic ADP-ribose-mediated signaling in the myocytes from small coronary arteries.
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Animals↗
Kinetics and hemodynamic effects of intravenous nicardipine modified by previous propranolol oral treatment.
Intravenous nicardipine, 5 mg, was administered in two comparable groups of eight patients with chronic coronary artery disease but no clinical signs of heart failure. One group had received no previous treatment and served as a control group, and the other had received long-term treatment with large oral doses of propranolol. Blood concentrations of nicardipine were higher, and the area under the plasma concentration curve was greater in the group previously treated by propranolol. The total clearance of nicardipine was decreased in patients taking propranolol, without a change in the half-life of the drug. Typical hemodynamic responses, namely, a decrease in aortic pressure and in arterial resistances, were greater and more lasting in patients previously treated orally by propranolol. Filling pressure remained stable in both groups. The nicardipine infusion did not induce signs of dromotropic or inotropic negative effects in either group. The greater and more lasting hemodynamic effects of nicardipine in the group previously treated orally by propranolol do not seem to be related to an overall hemodynamic action of propranolol, but are probably due to higher nicardipine plasma levels, and may be caused by a decrease in hepatic blood flow induced by propranolol, with a consequent decrease in nicardipine clearance and by a smaller nicardipine volume of distribution in the propranolol group.
Administration, Oral↗
Depressive symptoms among older adults: long-term reduction after a physical activity intervention.
We examined the effects of two physical activity modes on depressive symptoms over a 5-year period among older adults and change in physical self-esteem as a mediator of changes in depressive symptoms. Formerly sedentary, older adults (N = 174) were randomly assigned into 6-month conditions of either walking or low-intensity resistance/flexibility training. Depressive symptoms and physical self-esteem were measured before and after the 6-month intervention, and 12 and 60 months after intervention initiation. Depressive symptoms scores were decreased immediately after the intervention, followed by a sustained reduction for 12 and 60 months after intervention initiation; there was no differential pattern of change between the physical activity modes. Change in physical self-esteem predicted change in depressive symptoms. This study supports the effectiveness of an exercise intervention for the sustained reduction of depressive symptoms among sedentary older adults and physical self-esteem as a potential mediator of this effect.
Aged↗
Social cognitive correlates of leisure time physical activity among Latinos.
Despite the well-documented benefits of leisure time physical activity, Latinos are reported to be highest among all ethnic groups in leisure time inactivity. The present study examined the relationship between leisure time physical activity and exercise self-efficacy, exercise barriers self-efficacy, exercise social support, and perceived importance of physical activity. Data were obtained from 153 Latinos (n = 86 female, n = 67 male). Comparisons were made between Latinos with high and low levels of leisure time physical activity and between men and women. Results revealed that Latinos high in leisure time physical activity had significantly greater exercise and barriers self-efficacy, received more social support from friends to exercise, and placed greater importance on physical activity outcomes than did Latinos low in leisure time physical activity. No significant differences were revealed for social support from family, nor between men and women on the psychosocial variables. Physical activity interventions targeting sources of self-efficacy, increasing social support, and emphasizing the importance of regular physical activity should be helpful in increasing leisure time physical activity of Latinos. Future research should examine the influence of environmental and cultural variables on the leisure time physical activity of Latinos and how they interact with psychosocial factors.
Adult↗
Effects of aerobic fitness training on human cortical function: a proposal.
We briefly review the extant human and animal literature on the influence of fitness training on brain, cognition and performance. The animal research provides clear support for neurochemical and structural changes in brain with fitness training. The human literature suggests reliable but process specific changes in cognition with fitness training for young and old adults. We describe a research program which examines the influence of aerobic fitness training on the functional activity of the human using event-related functional magnetic resonance imaging, of humans in fitness interventions.
Adult↗