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Screening the system : exposing security clearance dangers
\"Screening the System shows how security clearance practices, including everything from background checks and fingerprinting to urinalysis and the polygraph, provide insight into the way we think about privacy, national security, patriotism, and the state\"-- Provided by publisher.
Book
Population Pharmacokinetics of Therapeutic Monoclonal Antibodies
A growing number of population pharmacokinetic analyses of therapeutic monoclonal antibodies (mAbs) have been published in the scientific literature. The aims of this article are to summarize the findings from these studies and to relate the findings to the general pharmacokinetic and structural characteristics of therapeutic mAbs. A two-compartment model was used in the majority of the population analyses to describe the disposition of the mAb. Population estimates of the volumes of distribution in the central (V
1
) and peripheral (V
2
) compartments were typically small, with median (range) values of 3.1 (2.4–5.5) L and 2.8 (1.3–6.8) L, respectively. The estimated between-subject variability in the V
1
was usually moderate, with a median (range) coefficient of variation (CV) of 26% (12–84%). Between-subject variability in other distribution-related parameters such as the V
2
and intercompartmental clearance were often not estimated. Although the pharmacokinetic models used most frequently in the population analyses were models with linear clearance, other models with nonlinear, or parallel linear and nonlinear clearance pathways were also applied, as many therapeutic mAbs are eliminated via saturable target-mediated mechanisms. Population estimates of the maximum elimination rate (V
max
) and the mAb concentration at which elimination was at half maximum for Michaelis-Menten-type elimination pathways varied considerably among the different therapeutic mAbs. However, estimates of the total clearance (CL) of mAbs with linear clearance characteristics and of the clearance of mAbs via the linear clearance pathway (CL
L
) with parallel linear and nonlinear clearance were quite similar for the different mAbs and typically ranged from 0.2 to 0.5 L/day, which is relatively close to the estimated clearance of endogenous IgG of 0.21 L/day. The between-subject variability in the V
max
, CL and CL
L
was moderate to high, with estimated CVs ranging from 15% to 65%. Measures of body size were the covariates most commonly identified as influencing the pharmacokinetics of therapeutic mAbs.
In summary, many features of the population pharmacokinetics of currently used therapeutic mAbs are similar, despite differences in their pharmacological targets and studied patient populations.
Journal Article
The influence of variable piston structure on the performance of magnetorheological dampers
Magnetorheological dampers (MRD) are widely used in many fields due to their fast response, high adjustability, and excellent vibration reduction performance. As a key component that directly affects the transmission of damping force within MRD, the optimization of the piston structure is of great significance for improving the damping adjustment range. In order to study the influence of piston structure on the damping performance of MRD output, a new type of MRD was designed based on the variable clearance piston structure in this paper. An experimental platform was built to test its performance under an external magnetic field. The damping clearance width D and piston plate length H were studied separately. The results showed that the maximum damping force that the damper with variable piston diameter D could output increased exponentially with the increase of D , while the maximum damping force that the damper with variable piston length H could output increased slowly with the increase of H .
Journal Article
Design of a Shield Tail Clearance Measuring Sensor for a Shield Machine
To improve the measurement accuracy and judge the distance between shield segments and shield tail accurately, the online monitoring technology of shield tail clearance was studied. Firstly, a sensor that can be used for shield tail clearance measurement was designed, and its key parts were selected. Secondly, the characteristics of the key parts were simulated to verify their feasibility. Finally, the monitoring principle was analyzed
Journal Article
Clearance of Amyloid Beta and Tau in Alzheimer’s Disease: from Mechanisms to Therapy
Alzheimer’s disease (AD) is the most common neurodegenerative disease. Pathological proteins of AD mainly contain amyloid-beta (Aβ) and tau. Their deposition will lead to neuron damage by a series of pathways, and then induce memory and cognitive impairment. Thus, it is pivotal to understand the clearance pathways of Aβ and tau in order to delay or even halt AD. Aβ clearance mechanisms include ubiquitin–proteasome system, autophagy-lysosome, proteases, microglial phagocytosis, and transport from the brain to the blood via the blood-brain barrier (BBB), arachnoid villi and blood-CSF barrier, which can be named blood circulatory clearance. Recently, lymphatic clearance has been demonstrated to play a key role in transport of Aβ into cervical lymph nodes. The discovery of meningeal lymphatic vessels is another direct evidence for lymphatic clearance in the brain. Furthermore, periphery clearance also contributes to Aβ clearance. Tau clearance is almost the same as Aβ clearance. In this review, we will mainly introduce the clearance mechanisms of Aβ and tau proteins, and summarize corresponding targeted drug therapies for AD.
Journal Article
A degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
PINK1-Parkin mediated mitophagy, a selective form of autophagy, represents one of the most important mechanisms in mitochondrial quality control (MQC) via the clearance of damaged mitochondria. Although it is well known that the conjugation of mammalian ATG8s (mATG8s) to phosphatidylethanolamine (PE) is a key step in autophagy, its role in mitophagy remains controversial. In this study, we clarify the role of the mATG8-conjugation system in mitophagy by generating knockouts of the mATG8-conjugation machinery. Unexpectedly, we show that mitochondria could still be cleared in the absence of the mATG8-conjugation system, in a process independent of lysosomal degradation. Instead, mitochondria are cleared via extracellular release through a secretory autophagy pathway, in a process we define as Autophagic Secretion of Mitochondria (ASM). Functionally, increased ASM promotes the activation of the innate immune cGAS-STING pathway in recipient cells. Overall, this study reveals ASM as a mechanism in MQC when the cellular mATG8-conjugation machinery is dysfunctional and highlights the critical role of mATG8 lipidation in suppressing inflammatory responses.
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
Journal Article
Experimental verification of dynamic behavior for multi-link press mechanism with 2D revolute joint considering dry friction clearances and lubricated clearances
The existence of clearance joints seriously affect the kinematic accuracy and service life of precision mechanisms. So as to ensure the kinematic accuracy reliability of mechanism, it is imperative to accurately predict the dynamic behavior of precision mechanism considering clearances. At present, the studies often focus on theoretical analysis and simulation verification of mechanism with clearances, while the studies verified by experiment are relatively few and often focus on simple mechanism. Moreover, most of studies centered on simple mechanism with dry friction clearance, while the studies on complex mechanism with multiple lubricated clearances are less. In this paper, the impact of multiple clearances on dynamic behavior of 2-DOF 9-bar precision press mechanism is analyzed. Firstly, the mathematical models of dry friction clearance and lubricated clearance are established and embedded into the Lagrange dynamic equation, respectively. Then, the impact of clearance values, the material of clearance-shaft and crank driving speeds on dynamic behavior of mechanism are researched. Finally, the simplified experimental platform of 2-DOF 9-bar press mechanism considering 2D revolute joint clearances is established, and the correctness of the theoretical model is proved by experimental verification. This study not only offers theoretical guidance for the layout and life prediction of multi-link press mechanism, but also provides reference for the dynamic behavior analysis and prediction of other mechanisms.
Journal Article
Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)
Early prediction of clearance mechanisms allows for the rapid progression of drug discovery and development programs, and facilitates risk assessment of the pharmacokinetic variability associated with drug interactions and pharmacogenomics. Here we propose a scientific framework – Extended Clearance Classification System (ECCS) – which can be used to predict the predominant clearance mechanism (rate-determining process) based on physicochemical properties and passive membrane permeability. Compounds are classified as: Class 1A – metabolism as primary systemic clearance mechanism (high permeability acids/zwitterions with molecular weight (MW) ≤400 Da), Class 1B – transporter-mediated hepatic uptake as primary systemic clearance mechanism (high permeability acids/zwitterions with MW >400 Da), Class 2 – metabolism as primary clearance mechanism (high permeability bases/neutrals), Class 3A –renal clearance (low permeability acids/zwitterions with MW ≤400 Da), Class 3B – transporter mediated hepatic uptake or renal clearance (low permeability acids/zwitterions with MW >400 Da), and Class 4 – renal clearance (low permeability bases/neutrals). The performance of the ECCS framework was validated using 307 compounds with single clearance mechanism contributing to ≥70% of systemic clearance. The apparent permeability across clonal cell line of Madin − Darby canine kidney cells, selected for low endogenous efflux transporter expression, with a cut-off of 5 × 10
−6
cm/s was used for permeability classification, and the ionization (at pH7) was assigned based on calculated pKa. The proposed scheme correctly predicted the rate-determining clearance mechanism to be either metabolism, hepatic uptake or renal for ~92% of total compounds. We discuss the general characteristics of each ECCS class, as well as compare and contrast the framework with the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS). Collectively, the ECCS framework is valuable in early prediction of clearance mechanism and can aid in choosing the right preclinical tool kit and strategy for optimizing drug exposure and evaluating clinical risk of pharmacokinetic variability caused by drug interactions and pharmacogenomics.
Journal Article
Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE
Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.
Journal Article
SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance
Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.
SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.
Journal Article