The Leeuwenhoek Lecture - The dynamics of viral functions

1961 ◽  
Vol 154 (954) ◽  
pp. 1-20 ◽  
Keyword(s):  
Molecular Dynamics ◽  
Infected Cell ◽  
Malignant Cell ◽  
Living Cells ◽  
Complex Structures ◽  
Complex Interplay ◽  
Lysogenic Bacterium ◽  
A Cell ◽  
Virus System ◽  
Viral Reproduction

The ultimate aim of biochemistry, wrote Sir Frederick Gowland Hopkins (1933), should be an adequate and acceptable description of molecular dynamics in living cells and tissues. My ambition, in this eleventh Leeuwenhoek Lecture, is to describe some aspects of the molecular dynamics of viral functions. A specific entity which is unable to multiply could not be a virus. The proper activity of a virus, the viral function par excellence, is consequently reproduction. Yet viral reproduction involves, not one, but a whole set of functions, for viruses, despite their reputation, are highly complex structures. In order that the lecture should not appear as the expression of an esoteric and impervious doctrinal corpus, we have to state first what we understand by the term virus, a necessary step in view of the fact that this is the fifth Leeuwenhoek Lecture dealing with viruses. It will also be necessary to explain the meaning of a very few unfamiliar terms. This done, a virus will be introduced into a cell and we shall try to understand how it develops. An infected cell may either die or survive. Sometimes a new balanced cell-virus system emerges, such as a lysogenic bacterium or a malignant cell. The complex interplay of cellular and viral functions will be analyzed. Then the current views concerning the mechanisms by which a cell regulates its functions will be summarized. This will lead finally to a discussion of the relation of viruses to regulating systems in general.

scholarly journals Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 334
Author(s):  
Shih-Ting Hong ◽  
Yu-Cheng Su ◽  
Yu-Jen Wang ◽  
Tian-Lu Cheng ◽  
Yeng-Tseng Wang
Keyword(s):  
Molecular Dynamics ◽  
Tnf Alpha ◽  
Complex Structures ◽  
Binding Characteristics ◽  
Accelerated Molecular Dynamics ◽  
Constant Ph ◽  
Ph Dependent ◽  
Constant Ph Molecular Dynamics ◽  
Antibody Drug

Humira is a monoclonal antibody that binds to TNF alpha, inactivates TNF alpha receptors, and inhibits inflammation. Neonatal Fc receptors can mediate the transcytosis of Humira–TNF alpha complex structures and process them toward degradation pathways, which reduces the therapeutic effect of Humira. Allowing the Humira–TNF alpha complex structures to dissociate to Humira and soluble TNF alpha in the early endosome to enable Humira recycling is crucial. We used the cytoplasmic pH (7.4), the early endosomal pH (6.0), and pKa of histidine side chains (6.0–6.4) to mutate the residues of complementarity-determining regions with histidine. Our engineered Humira (W1-Humira) can bind to TNF alpha in plasma at neutral pH and dissociate from the TNF alpha in the endosome at acidic pH. We used the constant-pH molecular dynamics, Gaussian accelerated molecular dynamics, two-dimensional potential mean force profiles, and in vitro methods to investigate the characteristics of W1-Humira. Our results revealed that the proposed Humira can bind TNF alpha with pH-dependent affinity in vitro. The W1-Humira was weaker than wild-type Humira at neutral pH in vitro, and our prediction results were close to the in vitro results. Furthermore, our approach displayed a high accuracy in antibody pH-dependent binding characteristics prediction, which may facilitate antibody drug design. Advancements in computational methods and computing power may further aid in addressing the challenges in antibody drug design.

scholarly journals Cytological studies on the viruses of fowl-pox and vaccinia

1928 ◽  
Vol 102 (719) ◽  
pp. 406-418 ◽  
Keyword(s):  
Life Cycle ◽  
Infected Cell ◽  
Living Cells ◽  
Histological Technique ◽  
The Subject ◽  
Nuclear Structures ◽  
Source Of Error

Although, as is well known, the ultra-microscopic viruses are invisible in histological preparations, yet characteristic bodies occur within certain of the cells of animals infected with such organisms. The origin and nature of these so-called “virus bodies” has been the subject of much controversy. By some they have been regarded as the actual parasite, or at least as phases in its life cycle. To von Prowazek they were dual in character consisting of microorganisms embedded in material produced by the reaction of the cytoplasm of the infected cell. Still other observers regarded such bodies as products of cellular disintegration. In a former paper (Findlay and Ludford (1926)) we have referred to the various views held by writers in this field and have made a survey of the literature of the subject in the form of a pictographic review. We shall, therefore, only mention previous work in this field, in so far as it directly concerns our personal observations. A conspicuous fault of much of the earlier work has been the unsatisfactory histological technique employed, especially the nature of the fixative. The earlier cytological work was carried out with fixatives, which although satisfactory for the subsequent demonstration of nuclear structures were very destructive to the cytoplasm. This is particularly unfortunate since most of the virus bodies occur in the ground cytoplasm of cells. We have endeavoured to rectify this source of error in our work by employing fixatives, which have been proved to fix the cells in such a manner as to give an appearance as nearly as possible identical with their structure, as seen in the living cells.

scholarly journals Methods and applications of label-free cell-based systems

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Joachim Wiest
Keyword(s):  
Environmental Monitoring ◽  
Morphological Changes ◽  
Free Cell ◽  
Living Cells ◽  
Label Free ◽  
Controlled System ◽  
Chip Technology ◽  
Cell Monitoring ◽  
A Cell ◽  
On Chip

Label-free monitoring of living cells is used in various applications such as drug development, toxicology, regenerative medicine or environmental monitoring. The most prominent methods for monitoring the extracellular acidification, oxygen consumption, electrophysiological activity and morphological changes of living cells are described. Furthermore, the intelligent mobile lab (IMOLA) – a computer controlled system integrating cell monitoring and automated cell cultivation – is described as an example of a cell-based system for microphysiometry. Results from experiments in the field of environmental monitoring using algae are presented. An outlook toward the development of an organ-on-chip technology is given.

scholarly journals A dual-labeling probe to track functional mitochondria–lysosome interactions in live cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qixin Chen ◽  
Hongbao Fang ◽  
Xintian Shao ◽  
Zhiqi Tian ◽  
Shanshan Geng ◽  
...  
Keyword(s):  
Fluorescence Intensity ◽  
Fluorescent Probes ◽  
Living Cells ◽  
Molecular Probe ◽  
Live Cells ◽  
Blue Fluorescence ◽  
Red Fluorescence ◽  
Dynamic Tracking ◽  
A Cell

AbstractMitochondria–lysosome interactions are essential for maintaining intracellular homeostasis. Although various fluorescent probes have been developed to visualize such interactions, they remain unable to label mitochondria and lysosomes simultaneously and dynamically track their interaction. Here, we introduce a cell-permeable, biocompatible, viscosity-responsive, small organic molecular probe, Coupa, to monitor the interaction of mitochondria and lysosomes in living cells. Through a functional fluorescence conversion, Coupa can simultaneously label mitochondria with blue fluorescence and lysosomes with red fluorescence, and the correlation between the red–blue fluorescence intensity indicates the progress of mitochondria–lysosome interplay during mitophagy. Moreover, because its fluorescence is sensitive to viscosity, Coupa allowed us to precisely localize sites of mitochondria–lysosome contact and reveal increases in local viscosity on mitochondria associated with mitochondria–lysosome contact. Thus, our probe represents an attractive tool for the localization and dynamic tracking of functional mitochondria–lysosome interactions in living cells.

scholarly journals Effect of Cyclic Stretch on Tissue Maturation in Myoblast-Laden Hydrogel Fibers

Micromachines ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 399 ◽  
Author(s):  
Shinako Bansai ◽  
Takashi Morikura ◽  
Hiroaki Onoe ◽  
Shogo Miyata
Keyword(s):  
Skeletal Muscle ◽  
Muscle Tissue ◽  
Skeletal Muscles ◽  
Malignant Tumors ◽  
Three Dimensional ◽  
Living Cells ◽  
Cyclic Stretch ◽  
Core Shell ◽  
Custom Made ◽  
A Cell

Engineering of the skeletal muscles has attracted attention for the restoration of damaged muscles from myopathy, injury, and extraction of malignant tumors. Reconstructing a three-dimensional muscle using living cells could be a promising approach. However, the regenerated tissue exhibits a weak construction force due to the insufficient tissue maturation. The purpose of this study is to establish the reconstruction system for the skeletal muscle. We used a cell-laden core-shell hydrogel microfiber as a three-dimensional culture to control the cellular orientation. Moreover, to mature the muscle tissue in the microfiber, we also developed a custom-made culture device for imposing cyclic stretch stimulation using a motorized stage and the fiber-grab system. As a result, the directions of the myotubes were oriented and the mature myotubes could be formed by cyclic stretch stimulation.

Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase

2019 ◽  
Vol 75 (6) ◽  
pp. 592-604 ◽  
Author(s):  
Marie Haufroid ◽  
Manon Mirgaux ◽  
Laurence Leherte ◽  
Johan Wouters
Keyword(s):  
Molecular Dynamics ◽  
Reaction Mechanism ◽  
Crystal Structures ◽  
Reaction Pathway ◽  
Living Cells ◽  
Homocysteic Acid ◽  
Phosphoserine Phosphatase ◽  
Key Enzyme ◽  
The Subject ◽  
Dynamics Simulations

The equilibrium between phosphorylation and dephosphorylation is one of the most important processes that takes place in living cells. Human phosphoserine phosphatase (hPSP) is a key enzyme in the production of serine by the dephosphorylation of phospho-L-serine. It is directly involved in the biosynthesis of other important metabolites such as glycine and D-serine (a neuromodulator). hPSP is involved in the survival mechanism of cancer cells and has recently been found to be an essential biomarker. Here, three new high-resolution crystal structures of hPSP (1.5–2.0 Å) in complexes with phosphoserine and with serine, which are the substrate and the product of the reaction, respectively, and in complex with a noncleavable substrate analogue (homocysteic acid) are presented. New types of interactions take place between the enzyme and its ligands. Moreover, the loop involved in the open/closed state of the enzyme is fully refined in a totally unfolded conformation. This loop is further studied through molecular-dynamics simulations. Finally, all of these analyses allow a more complete reaction mechanism for this enzyme to be proposed which is consistent with previous publications on the subject.

scholarly journals Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

2019 ◽  
Vol 15 ◽  
pp. 1933-1944 ◽  
Author(s):  
Silvie Rimpelová ◽  
Michal Jurášek ◽  
Lucie Peterková ◽  
Jiří Bejček ◽  
Vojtěch Spiwok ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Biological Effects ◽  
Sesquiterpene Lactones ◽  
Living Cells ◽  
Calcium Atpase ◽  
Dynamics Simulation ◽  
Plant Metabolites ◽  
Cytotoxic Effects ◽  
Secondary Plant Metabolites ◽  
Fluorescent Derivative

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide–alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

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