The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal ...excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT3 receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT3 receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT3 receptors have identified a novel domain (the intracellular MA-stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the receptor has revealed residues, within the principle (A–C) and complementary (D–F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT3 receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5-HT3 receptor function, or expression, and consider their relevance to (patho)physiology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Research has indicated that the child care center is a very strong predictor of preschool-aged children's physical activity levels, making this an important setting to help young children obtain ...physical activity that is appropriate for their health and development. However, some evidence suggests that organized child care may not adequately support children's physical activity needs. Although many organizations provide recommendations, guidelines, or standards for motor skill development and physical activity opportunities, no set of guidelines exist that directly target the overall physical activity environment at child care. Because of the lack of comprehensive recommendations, the Nutrition and Physical Activity Self-assessment for Child Care best-practice guidelines for healthy weight development were created on the basis of an extensive review of existing guidelines, research evidence, and expert review. The purpose of this article is to present these physical activity best-practice guidelines and provide data on how these guidelines compare to current practice in a large sample (N = 96) of child care centers in North Carolina. These best-practice guidelines include recommendations for 8 unique components of the child care environment, including active opportunities, fixed play environment, portable play environment, sedentary opportunities, sedentary environment, staff behavior, staff training/education, and physical activity policies. Our results showed that only a few of the best-practice guidelines were achieved by a majority of the 96 North Carolina child care centers that participated in this study. Establishing comprehensive guidelines for physical activity at child care could result in higher activity levels and healthier children, but more research is needed.
T4 DNA ligase is a widely used ligase in many applications; yet in single nucleotide polymorphism analysis, it has been found generally lacking owing to its tendency to ligate mismatches quite ...efficiently. To address this lack of selectivity, we explored the effect of temperature on the selectivity of the ligase in discriminating single base pair mismatches at the 3′‐terminus of the ligating strand using short ligation probes (9‐mers). Remarkably, we observe outstanding selectivities when the assay temperature is increased to 7 °C to 13 °C above the dissociation temperature of the matched probe:target duplexes using commercially available enzyme at low concentration. Higher enzyme concentration shifts the temperature range to 13 °C to 19 °C above the probe:target dissociation temperatures. Finally, substituting the 5′‐phosphate terminus with an abasic nucleotide decreases the optimal temperature range to 7 °C to 10 °C above the matched probe:target duplex. We compare the temperature dependence of the T4 DNA ligase catalyzed ligation and a nonenzymatic ligation system to contrast the origin of their modes of selectivity. For the latter, temperatures above the probe:target duplex dissociation lead to lower ligation conversions even for the perfect matched system. This difference between the two ligation systems reveals the uniqueness of the T4 DNA ligase's ability to maintain excellent ligation yields for the matched system at elevated temperatures. Although our observations are consistent with previous mechanistic work on T4 DNA ligase, by mapping out the temperature dependence for different ligase concentrations and probe modifications, we identify simple strategies for introducing greater selectivity into SNP discrimination based on ligation yields.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Accumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how intraneuronal Tau levels are regulated in health and disease remains unclear. Here, we ...show that conditional inactivation of the trafficking adaptor protein Numb in retinal ganglion cells (RGCs) increases Tau levels and leads to axonal blebbing, which is followed by neuronal cell loss in aged mice. In the TauP301S mouse model of tauopathy, conditional inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and loss of Numb in motoneurons also leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72) decreases intracellular Tau levels and reduces axonal blebbing in TauP301S RGCs, leading to improved electrical activity in cultured neurons and improves performance in a visually guided behavior test in vivo. These results uncover Numb as a key regulator of intracellular Tau levels and identify Numb-72 as a potential therapeutic factor for tauopathies.
The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal ...excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT3 receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT3 receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT3 receptors have identified a novel domain (the intracellular MA-stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the receptor has revealed residues, within the principle (A-C) and complementary (D-F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT3 receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5-HT3 receptor function, or expression, and consider their relevance to (patho)physiology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
The 5-hydroxytryptamine type-3 (5-HT sub(3)) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT sub(3) receptor activation in the central and peripheral nervous systems ...evokes neuronal excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT sub(3) receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT sub(3) receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT sub(3) receptors have identified a novel domain (the intracellular MA- stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the receptor has revealed residues, within the principle (A-C) and complementary (D-F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT sub(3) receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5- HT sub(3) receptor function, or expression, and consider their relevance to (patho)physiology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Human epidermal growth factor receptor 2 (HER2) overexpression is present in approximately 15% of early invasive breast cancers, and is an important predictive and prognostic marker. The substantial ...benefits achieved with anti-HER2 targeted therapies in patients with HER2-positive breast cancer have emphasised the need for accurate assessment of HER2 status. Current data indicate that HER2 test accuracy improved following previous publication of guidelines and the implementation of an external quality assessment scheme with a decline in false-positive and false-negative rates. This paper provides an update of the guidelines for HER2 testing in the UK. The aim is to further improve the analytical validity and clinical utility of HER2 testing by providing guidelines of test performance parameters, and recommendations on the postanalytical interpretation of test results. HER2 status should be determined in all newly diagnosed and recurrent breast cancers. Testing involves immunohistochemistry with >10% complete strong membrane staining defining a positive status. In situ hybridisation, either fluorescent or bright field chromogenic, is used either upfront or in immunohistochemistry borderline cases to detect the presence of HER2 gene amplification. Situations where repeat HER2 testing is advised are outlined and the impact of genetic heterogeneity is discussed. Strict quality control and external quality assurance of validated assays are essential. Testing laboratories should perform ongoing competency assessment and proficiency tests and ensure the reliability and accuracy of the assay. Pathologists, oncologists and surgeons involved in test interpretation and clinical use should adhere to published guidelines and maintain accurate performance and consistent interpretation of test results.
Multidetector computed tomographic angiography (CTA) was evaluated alone and with imaging of the pelvic and thigh veins (CTA–CTV). As compared with a reference standard for the diagnosis of acute ...pulmonary embolism, CTA–CTV had a higher sensitivity than CTA alone, with similar specificity.
Multidetector computed tomographic angiography (CTA) was evaluated alone and with imaging of the pelvic and thigh veins (CTA–CTV). CTA–CTV had a higher sensitivity than CTA alone, with similar specificity.
Uncertainty persists about the accuracy of contrast-enhanced multidetector computed tomographic angiography (CTA) for the diagnosis of pulmonary embolism. The sensitivity of single-slice CTA has ranged from 60
1
to 100
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percent, and the specificity has ranged from 81
1
to 100
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percent. A previous review focused on the diagnostic accuracy of single-slice CTA.
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Visualization of segmental and subsegmental pulmonary arteries is substantially better with four-slice CTA and thin collimation (1.25 mm) than with single-slice CTA.
5
,
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In two studies of fewer than 100 patients, sensitivities for the detection of pulmonary embolism with four-slice CTA have been reported to be 96 percent
7
and . . .
Objective Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date ...examining cerebrospinal fluid AD biomarkers in AA individuals. Methods We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non‐AD cases, including 495 (16.5%) self‐identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data‐driven multivariate Gaussian mixture of regressions. Results Distinct effects of race were found in different groups. Total Tauand phospho181‐Tau were lower among AA individuals in all groups ( p < 0.0001), and Aβ 42 was markedly lower in AA controls compared with white controls ( p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2‐decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker‐positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%). Interpretation Although the risk of dementia is higher, data‐driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024
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