The Role of In Vitro–In Vivo Correlation in Product Development and Life Cycle Management

2007 ◽  
pp. 71-105 ◽  
Author(s):  
Shoufeng Li ◽  
Martin Mueller-Zsigmondy ◽  
Hequn Yin
Keyword(s):  
Life Cycle ◽  
Product Development ◽  
Life Cycle Management

scholarly journals How the spleen reshapes and retains young and old red blood cells: A computational investigation

2021 ◽  
Vol 17 (11) ◽  
pp. e1009516
Author(s):  
He Li ◽  
Zixiang Leonardo Liu ◽  
Lu Lu ◽  
Pierre Buffet ◽  
George Em Karniadakis
Keyword(s):  
Life Cycle ◽  
Computational Study ◽  
Lymphoid Organ ◽  
Biological Processes ◽  
Immune Functions ◽  
Computational Investigation ◽  
Underlying Mechanisms

The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell’s (RBC) life cycle. Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar “pitting” process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed in vivo or in vitro and offer insights into the role of the spleen in the RBC physiology.

scholarly journals Phyto-oestrogens through the life cycle

2000 ◽  
Vol 59 (3) ◽  
pp. 489-496 ◽  
Author(s):  
Aedin Cassidy ◽  
Marian Faughnan
Keyword(s):  
Life Cycle ◽  
Human Health ◽  
Intestinal Microflora ◽  
Human Subjects ◽  
Epidemiological Data ◽  
Potential Health ◽  
Wide Range

The growing interest in the role of phyto-oestrogens in human health has prompted scientists to evaluate the risk : benefit which would result from consuming high levels of these compounds at different stages of the life cycle. These compounds have been shown to exert a wide range of hormonal and non-hormonal activities in animals and in vitro, and these activities suggest plausible mechanisms for potential health effects in human subjects consuming phyto-oestrogen-rich diets. In addition, experimental and epidemiological data are available supporting the concept that phyto-oestrogen-rich diets exert physiological effects in vivo; however, their relative importance to human health remains to be elucidated. Our understanding of factors involved in their absorption and metabolism, including the role of intestinal microflora, is limited, and these factors together with dose-related effects may well be important in determining clinical efficacy.

scholarly journals Deletion of Murid Herpesvirus 4 ORF63 Affects the Trafficking of Incoming Capsids toward the Nucleus

2015 ◽  
Vol 90 (5) ◽  
pp. 2455-2472 ◽  
Author(s):  
Muhammad Bilal Latif ◽  
Bénédicte Machiels ◽  
Xue Xiao ◽  
Jan Mast ◽  
Alain Vanderplasschen ◽  
...  
Keyword(s):  
Life Cycle ◽  
Immune Evasion ◽  
Tegument Proteins ◽  
Animal Populations ◽  
Animal Pathogens ◽  
Herpesvirus 4 ◽  
Growth Deficit

ABSTRACTGammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. This is especially true for tegument proteins. Interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by Kaposi's sarcoma-associated herpesvirus open reading frame 63 (ORF63). To gain insight about the roles of ORF63 in the life cycle of a gammaherpesvirus, we generated null mutations in the ORF63 gene of murid herpesvirus 4 (MuHV-4). We showed that disruption of ORF63 was associated with a severe MuHV-4 growth deficit bothin vitroandin vivo. The latter deficit was mainly associated with a defect of replication in the lung but did not affect the establishment of latency in the spleen. From a functional point of view, inhibition of caspase-1 or the inflammasome did not restore the growth of the ORF63-deficient mutant, suggesting that the observed deficit was not associated with the immune evasion mechanism identified previously. Moreover, this growth deficit was also not associated with a defect in virion egress from the infected cells. In contrast, it appeared that MuHV-4 ORF63-deficient mutants failed to address most of their capsids to the nucleus during entry into the host cell, suggesting that ORF63 plays a role in capsid movement. In the future, ORF63 could therefore be considered a target to block gammaherpesvirus infection at a very early stage of the infection.IMPORTANCEThe important diseases caused by gammaherpesviruses in human and animal populations justify a better understanding of their life cycle. In particular, the role of most of their tegument proteins is still largely unknown. In this study, we used murid herpesvirus 4, a gammaherpesvirus infecting mice, to decipher the role of the protein encoded by the viral ORF63 gene. We showed that the absence of this protein is associated with a severe growth deficit bothin vitroandin vivothat was mainly due to impaired migration of viral capsids toward the nucleus during entry. Together, our results provide new insights about the life cycle of gammaherpesviruses and could allow the development of new antiviral strategies aimed at blocking gammaherpesvirus infection at the very early stages.

scholarly journals Role of Outer Surface Protein D in the Borrelia burgdorferi Life Cycle

2007 ◽  
Vol 75 (9) ◽  
pp. 4237-4244 ◽  
Author(s):  
Xin Li ◽  
Girish Neelakanta ◽  
Xianzhong Liu ◽  
Deborah S. Beck ◽  
Fred S. Kantor ◽  
...  
Keyword(s):  
Life Cycle ◽  
Borrelia Burgdorferi ◽  
Outer Surface ◽  
Murine Model ◽  
Blood Meal ◽  
Ixodes Scapularis ◽  
Surface Protein

ABSTRACT Borrelia burgdorferi preferentially induces selected genes in mice or ticks, and studies suggest that ospD is down-regulated in response to host-specific signals. We now directly show that ospD expression is generally elevated within Ixodes scapularis compared with mice. We then assessed the importance of OspD throughout the spirochete life cycle by generating OspD-deficient B. burgdorferi and examining the mutant in the murine model of tick-transmitted Lyme borreliosis. The lack of OspD did not influence B. burgdorferi infectivity in mice or the acquisition of spirochetes by I. scapularis. OspD adhered to tick gut extracts in vitro, and the OspD-deficient B. burgdorferi strain had a threefold decrease in colonization of the tick gut in vivo. This decrease, however, did not alter subsequent spirochete transmission during a second blood meal. These data suggest that B. burgdorferi can compensate for the lack of OspD in both ticks and mice and that OspD may have a nonessential, secondary, role in B. burgdorferi persistence within I. scapularis.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

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