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I need someone to write a high-quality review article on Smart City Knowledge Models and Ontologies.
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Feb 1, 2018
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Jan 30, 2018
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Requiring an expert UI/UX app design for app layout. Multi-functions including:
Login/Logout/Forgot Password
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Payment with Stripe (a payment gateway), code (barcode/QR/Text code) generation
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Jan 28, 2018
Jan 28, 20182d 12h
We need a system administrator/coder who is proficient at the LINUX / NGINX / MYSQL / PHP/ DRUPAL / DRUSH.
The job includes system administration, PHP coding, MYSQL database and other work to build a commodities exchange site that is already at proof of concept.
Jan 28, 2018
Jan 28, 20182d 8h
First, let me make some suggestions.
I will pay the total development cost by installment.
And starting February 28, monthly installment payment of $ 100 begins.
For example, if the total development cost is 4000 $, it takes 40 months to pay it.
The website must be completed within 50 days at the latest.
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Jan 27, 2018
Jan 27, 20181d 7h
I need to create instance, install my magento theme with with this requirements:
Load Balance
Cloud Sql (my database of cms magento)
Pagespeed on Apache
CDN Cloudflare
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I have written about 120 &high level& business requirements for an iOS social app that I have in mind.
I am looking for a highly skilled InVision wireframes expert (not beginner!) who can produce a CLEAR design for the iOS application. There are so many shitty designs out there - this one cannot be that. You must have an artistic touch, not just a technical expert who does UI on the sid...
Jan 26, 2018
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I want an article on Marriage licence requirements
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I want someone that has a good understanding of NF525 that can explain what software is affected and the process of certification. You have to speak good [url removed, login to view] where you will explain this to me.
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We are a Design company, Elactis SA situated in Gebeva Switz. , part of the Gevasol group.
Jan 22, 2018
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the data below would be customers MENU for their products DATABASE, I would need to add &Categories id& into the equation also.
this would be [url removed, login to view] Where I would have a MENU ADDED, Next to the REVIEW BUTTON.
With CodeIgniter can you grab the products modules from, Controllers, models, views and helpers from that listing site that has products? and add C...
Jan 20, 2018
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Salesforce - set up a sales platform with our requirements.
Use - sales force lighteing edition.
We are a tech solution provider to the UK lettings industry.
We would liek someone to set up the sales force crm system including tasks below:
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Set up automated reports
Set up mailchimp integration
Set up mapping for auto upload of data to leads.
Jan 20, 2018
Jan 20, 20187d 23h
I am currently looking for a professional from United States to write business requirements in native English.
Technical background is needed.
Please send me a message if you can help with this.
NOTE: I am looking for an United States citizen. Other candidates, please don't apply.
Otherwise, I will report.
Jan 19, 2018
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I require a highly skilled graphical designer with experience in book layouts - specifically one that has experience with Amazon Kindle & Amazon publishing Paper back.
The job includes designing the Kindle book and Paperback using provided illustrations and text and preparing them for submission according to Amazon submission requirements for publishing.
Job will be complete when i approve t...
Jan 19, 2018
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Need research for what cosmetic packaging has to have on it for an eyeshadow palette in order to be sold in US and help on what I need to put on mine as well as naming 28 eyeshadow colors based on theme ans demographic.
Jan 18, 2018
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I need a new website. I need you to design and build a landing page. Previous experience with building a real estate related website is an asset
Jan 15, 2018
Jan 15, 2018Ended
Automated Testing Procedure to measure Audio Response and Phase Angle of electronics.
Stanford Research SR830 Lock-In amplifier interfaced with RS-232 interface to Win 7 or 8 or 10 computer.
SR-830 Lock In amplifier to sweep sinewave from 10Hz to 30,000Hz.
Data plotted in Graphical form for printout or inclusion into txt documents.
Low cost interface program. (prefer to use Labview)...
Jan 15, 2018
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你可能喜欢Once upon a time the cell membranes: 175 years of cell boundary research | SpringerLink
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Once upon a time the cell membranes: 175 years of cell boundary researchJonathan LombardOpen AccessReview
Part of the following topical collections:All modern cells are bounded by cell membranes best described by the fluid mosaic model. This statement is so widely accepted by biologists that little attention is generally given to the theoretical importance of cell membranes in describing the cell. This has not always been the case. When the Cell Theory was first formulated in the XIXth century, almost nothing was known about the cell membranes. It was not until well into the XXth century that the existence of the plasma membrane was broadly accepted and, even then, the fluid mosaic model did not prevail until the 1970s. How were the cell boundaries considered between the articulation of the Cell Theory around 1839 and the formulation of the fluid mosaic model that has described the cell membranes since 1972? In this review I will summarize the major historical discoveries and theories that tackled the existence and structure of membranes and I will analyze how these theories impacted the understanding of the cell. Apart from its purely historical relevance, this account can provide a starting point for considering the theoretical significance of membranes to the definition of the cell and could have implications for research on early life.This article was reviewed by Dr. ?tienne Joly, Dr. Eugene V. Koonin and Dr. Armen Mulkidjanian.Cell membrane discovery Cell membrane structure Cell Theory History of Science Cell definition Origins of life Early evolution Cenancestor
article PDFModern descriptions of the cell are intimately related to the notion of cell membranes. The cell membrane is not only the boundary of the unit of life, it is also a specific compartment that harbors many essential cell functions including communication with the environment, transport of molecules and certain metabolic functions. Nowadays, the consensual model to depict the membrane structure and functions is called the “fluid mosaic model” [].The fluid mosaic hypothesis was formulated by Singer and Nicolson in the early 1970s []. According to this model, membranes are made up of lipids, proteins and carbohydrates (Figure ). The main lipid membrane components are phospholipids. These molecules are amphiphilic, i. e. they have one polar part attracted by water (hydrophilic) and one apolar component repelled by water (hydrophobic). When they are diluted in water, amphiphiles spontaneously adopt the most thermodynamically stable molecular structure, namely the one that maximizes both hydrophilic and hydrophobic interactions []. These interactions may be affected by several parameters, such as the chemical nature of the molecules, their size, the salinity and pH of the solution. In biological conditions, cell phospholipids form a bilayer in which hydrophobic tails face each other in the core of the structure whereas the hydrophilic heads interact with the surrounding water (Figure ). Since proteins are also amphiphilic molecules, the same constraints apply to them. Some proteins (called intrinsic or integral) are embedded in the lipid bilayer matrix where they are able to establish hydrophobic and hydrophilic interactions with their respective lipid counterparts. Other proteins, called extrinsic or peripheral proteins, can also be transiently associated with membrane surfaces through weaker interactions (Figure ). Finally, carbohydrates can be linked to either proteins or lipids, resulting in glycoproteins or glycolipids.
Figure 1 Fluid mosaic model. Schematic view of biological membrane structure as currently depicted. The “mosaic” term of this model refers to the mixture of lipids and intrinsic proteins in the membrane. These boundaries are also “fluid” because their components can move laterally, allowing both diffusion of components and local specific gatherings. Other lipids, such as cholesterol, act as membrane fluidity regulators. Phospholipid movements are generally restricted to lateral drift, because the cross of the membrane from one side to the other requires the energetically unfavorable transient contact of their hydrophilic head with the hydrophobic membrane core. Thus, the transfer of molecules from one side of the membrane to the other generally involves the activity of some specific integral membrane proteins, called flippases []. For the same reasons, integral proteins can diffuse within the lipid matrix but they seldom switch their polarity from one membrane side to the other. As a result, lipid, protein and carbohydrate composition are different between the two monolayers, a characteristic that is referred to as membrane asymmetry.Membrane functions are extremely diverse. As cell borders, membranes control the molecular exchanges with the environment, resulting in cell pH regulation and osmotic homeostasis. Membranes are “selective barriers”: They concentrate nutrients within the cell, exclude the cellular waste products, keep the ionic gradients and transform them into chemical energy. Since they allow the transduction of many external stimuli into cell signals, they are also major actors in the responses of the cell to their environment. In addition, their composition also turns membranes into the main apolar compartment of the prominently aqueous cell medium, thus concentrating most lipid pigments (e.g. chlorophyll) and hydrophobic proteins. The presence of these molecules in the membranes doubles their bounding function with essential metabolic and bioenergetic activities.Except for some rare authors who still envisage the cell as a naked colloid network [], there is nowadays little disagreement that membranes are essential parts of all contemporary cells. Despite this basic acceptance concerning modern cells, we have witnessed in recent years a strong debate questioning the presence of similar membranes in the last common ancestor of living organisms, namely the cenancestor. Arguing about the presence or absence of membranes in early organisms–not only the cenancestor, but also previous organisms closer in time to the origins of life–challenges what we consider to be the basic unit of life, i.e. the cell. Unfortunately, because the lack of membranes is generally unquestioned in modern organisms, it is nowadays difficult to come across discussions about the theoretical importance of membranes.The limited attention currently given to membranes in defining the cell concept contrasts greatly with the importance that this issue had in early cell studies. Indeed, when the Cell Theory was formulated 175 years ago in the XIXth century, the reality of the membrane was unknown. Its universal character was not generally acknowledged until well into the XXth century, and even when the cells were assumed to be bounded by some kind of membrane, the fluid mosaic model was not accepted until as late as the 1970s. The natural question then is: how were the cell boundaries envisioned between the formulation of the Cell Theory around 1839 and the final predominance of the fluid mosaic model in 1972? In this review, I will provide some answers to this question that I think will be useful in three different ways. First, it will considerably extend the range of some recent publications [],[] in order to provide a more complete account of the discovery of membranes Second, I will suggest that, contrary to the ideas favored in some articles, the discovery of biological membranes was not quite as a linear cumulative process as it has bee And third, I expect that the acknowledgment of the importance of the cell boundary concept on modern conceptions of the cell will provide a fertile ground for discussions about the membranes in ancestral organisms. This, I hope, will open new perspectives for the stimulating field of the origins of life.In the next sections, I will review the main discoveries that led to our current model of biological membranes: (1) the long path from the original assumptions about cell boundaries in the early Cell Theory to the first evidence that supported the ex (2) early studies on cel (3) how evidence from permeability studies progressively built an alternative vision of cell boundaries–distinct from the model favored in the field and (4) how the fluid mosaic model came into being. As shown in the sections below, many authors coming from different fields contributed to our understanding of membranes along the centuries. The reader will find a timeline summarizing the most dramatic contributions to membrane knowledge up to 1972 in Figures
Figure 2 Timeline . Summary of the main contributions related to cell membrane discovery between the coining of the term “cell” in biology and the first studies on cell membrane structures. The events are approximatively ordered from top to bottom from the earlier events to the most recent. Although the studies are sometimes difficult to classify, the colors of the boxes reflect some major research axes influent to this history: dark blue, doubts about the existen orange, red, studies with
purple, ele dark green, direct description of membranes. Although most of these contributions were highly interconnected, full lines between boxes highlight particularly important relationships and dashed lines point out to contradictory views in major controversies.
Figure 3 Timeline . Summary of the main contributions related to cell membrane discovery between the first studies on cell membrane structures and the formulation of the fluid mosaic model. The events are approximatively ordered from top to bottom from the earlier events to the most recent. Although the studies are sometimes difficult to classify, the colors of the boxes reflect some major research axes influent to this history: orange, red, studies with
purple, ele dark green, direct desc pink, some
light blue, asymmetric ion light green, electron microscopy studies. Although most of these contributions were highly interconnected, full lines between boxes highlight particularly important relationships and dashed lines point out to contradictory views in major controversies. It is surprising to note that most short accounts of cell membrane discovery barely discuss the early controversies on the existence of membranes around the cells []-[]. On the one hand, most papers dealing with the characterization of membranes assume that cell membranes were a corollary of the Cell Theory. On the other hand, many authors studying the Cell Theory consider the mere osmotic or permeability studies of the late XIXth century to be sufficient in extinguishing previous reluctances to the existence of membranes. In this section, we will see that the existence of plasma membranes seemed to be an unnecessary postulate for most of the XIXth century. Only at the turn of the XXth century, the existence of membranes became a convenient assumption for the study of most cell processes. The issue was not settled until molecular descriptions became more precise in the mid-XXth century.The construction of the cell concept was a complex process that spanned the work of a large number of naturalists from the XVIIth to the XIXth centuries [],[]. Since it is not my intention here to discuss the history of the Cell Theory, I will only deal with those authors whose work was particularly relevant for their conceptions of cell membranes (see dark blue boxes in Figure ). Because many authors of this period wrote in German, the citations in the following sections will include both the primary and the secondary documents that I used to prepare this review.In 1665, Hooke observed a piece of cork with his microscope and saw cavities that he compared to honey combs []. He named these cavities “cells”. This name is revealing because from the start it suggests the existence of some borders limiting an empty space. Yet, the cell boundaries that Hooke and his contemporaries could easily observe with their microscopes were the plant cell walls. Nowadays, we know that many cells can be surrounded by hard cell walls which are different from the universal cell membranes. However, since only cell walls could be easily observed at that time, early debates among microscopists focused on these structures for over 150 years.During that period, two different conceptions of the microscopic observations competed with each other. On the one hand, some authors thought that the cell walls were continuous structures spanning the plant organism. Although he had first described the parenchyma of plants as a “mass of bubbles” [], Grew was later the first to embrace the opinion that cell walls were made up of fibers woven together in a structure comparable to a textile fabric [] –incidentally, giving rise to the introduction of the term “tissue” in biology []. This line of thought lasted until the early XIXth its last proponent was Mirbel, who assumed that the whole plant organism was made of a unique membranous structure (note here that the terms “membrane” and “cell wall” were indistinctly used at that time). From his point of view, the “cells” that were observed among the “membranes” were also thought to be parts of a continuous cavity []. To quote one of his opponents, Mirbel’s cells were like “the bubbles in the bread crumb” []. On the other hand, many authors, the first of whom was Malpighi, envisioned the cells not just as the space between the “membranes” but as discrete structures bounded by cell walls [],[]. The latter hypothesis was eventually accepted in the early XIXth century when Treviranus, Moldenhawer and Dutrochet managed to separate the cells from the plant tissue using different methods [],[],[],[]. Link’s demonstration that pigments from one cell did not pass into neighboring cells unless the cell walls were broken also contradicted Mirbel’s assumption that cavities formed a continuous compartment [],[]. By the first quarter of the XIXth century, plant cells were widely acknowledged as unconnected utricules bounded by separate cell walls []. Yet, the distinction between cell walls and cell membranes remained impossible.The finding that plant cells could be separated from plant tissues contributed in shaping the increasingly popular idea that all organisms were made up of cells, namely the Cell Theory. Many biology manuals credit Schleiden and Schwann for the formulation of this theory. More thorough historical analyses actually show that the idea that cells were universal structures predated these authors and most of the features that we now recognize as cell-defining were discovered after Schleiden and Schwann [],[]. Nevertheless, Schleiden and Schwann’s contributions were highly influential because they were among the first to intrinsically relate the idea of the universality of cells to the universality of their multiplication and growth. Their point of view on cell development deserves specific attention from us because it impacted the way people thought about cell membranes for the rest of the XIXth century.In 1837, Schleiden postulated a common development mechanism for all plant cells [],[]. Two years later, in 1839, Schwann enriched and extended Schleiden’s hypothesis to animal cells, thus suggesting that there was an universal mechanism for cell development [],[]. Their hypothesis was as follows (Figure ): All living cells were made up of an amorphous substance called cytoblastema from which cells originated. The main difference between their respective hypotheses was that Schleiden thought that new cells always grew inside other cells, whereas Schwann acknowledged the possibility that cells could grow from any cytoblastema— whether internal or external. According to both authors, the first step for the formation of a new cell would have been the coagulation of a part of a preexisting cytoblastema into a nucleolus. The nucleolus would have acted as a nucleation center that would incorporate other molecules from the cytoblastema in a process similar to mineral crystallization. During growth, a differentiation process would have allowed the separation of the nucleus from the rest of the cell. Hardened membranes around the nucleus and the cell emerged as the result of the contact between two “phases”, i.e. the nucleus/cytoplasm or cytoplasm/environment, respectively. Although Schleiden did not discuss membranes much, Schwann considered them to be important structures responsible for separating the cell from its environment, and to be the place where “fermentation” (metabolism) took place. He assumed that membranes always limited the cells, even when they were invisible, and he suggested that the existence of membranes could be inferred from the internal Brownian movement of cell components, which did not cross the cell borders.
Figure 4 The development of cells according to Schleiden. This figure has been drawn for clarity from descriptions by Schleiden and Schwann, but these authors never tried to provide such a synthetic depiction in their work. Schwann’s model was very similar, except for his opinion that new cells could also crystallize from cytoblastema outside previous cells. Despite the fact that Schleiden and Schwann’s models proved to be wrong, they acted as catalysts to foster hot debates about cell multiplication and organization that dominated histology for the rest of the century. Regarding the cell membranes, there are several points to keep in mind for the next section: First, even though Schwann assigned them essential roles, his conception of cell membranes as hardened interface structures is completely different from our current knowledge of the subject. Second, it must be recalled that, at the time, it was still impossible to make the distinction between the cell membran some people tried to look for cell walls in animal tissues and make comparisons between plant cell walls and other animal external structures, but their results were confusing []. Finally, many of his contemporaries called into question the assumption that, even when invisible, membranes always bounded the cells: this seemed to be theoretically unnecessary and hard to prove. As it will be developed in the next section, those who–correctly–recognized the lack of an animal equivalent to the plant cell wall predominantly assumed that membranes were not a mandatory characteristic of all cells.The second half of the XIXth century was a period of many fascinating biological debates and discoveries related to the Darwinian evolution, the physiology of both animal and plants and, even in histology, the discovery of mitosis. Within this context, the cell boundaries received relatively limited attention. By the early 1890s, cell membranes were often thought to be unessential secondary structures [].Although some authors had already thought of the cell membranes as optional secondary structures [],[],[], it seems that the first author who explicitly dismissed the existence of cell membranes was Leydig in 1857 [],[]. He based his opinion in the fact that membranes were not always observable and depicted the cell simply as a “substance primitively approaching a sphere in shape and containing a central body called a kernel [nucleus]” []. He recognized the existence of membranes as secondary structures resulting from the hardening of the cell surface. Later on, studies on amoebas reinforced the opinion that cell walls were not necessary characteristics of cells: De Bary, who understood the cell boundaries to be a solid structure like the cell walls, observed in Plasmodium several nuclei with no partition around each of them. He concluded that membranes may exist or not depending on different cell types [],[]. He also reasonably argued that the presence of a rigid cell wall would have prevented the protoplasm contraction that allowed the amoeboid movements in his model organisms. In a similar way, Haeckel agreed that bounding membranes were facultative in protists [],[].In the second half of the XIXth century, the main opponent to the existence of membranes around cells was the protistologist Max Schultze [],[],[],[],[]. This author described the cells as small lumps of contractile protoplasm that held together because of their inability to mix with water. In his opinion, membranes were only secondary structures resulting from the hardening of the cell surface. Their appearance was an artifact that marked the beginning of the degeneracy of protists. When membranes existed, they impeded the cell division and the internal protoplasmic movements, resulting in a loss of cellular activity. Beale accordingly viewed the appearance of membranes as a mark of natural degeneracy that differentiated the active, living protoplasm from the inactive, dead material produced by the cell []. In 1890, Turner published a review that explored the history and updates to the Cell Theory []. He described plasma membranes as being secondary structures and extended this idea to their intracellular counterparts based on the fact that the nuclear membrane disappeared during mitosis. In this context, it is not surprising that Schultze and later Sachs argued for the absurdity of the very term “cell” [],[],[]. The original term coined by Hooke stressed the existence of the cell walls, whereas these authors acknowledged the protoplasm (the protoplast, according to Hanstein, [],[]) as the seat of biological activities.Interestingly, although many authors from this period took for granted the absence of cell membranes, this was also the era of the first osmotic studies. Speculations about cell borders remained intact because the histological observations could not find a difference between specific cell membranes and the simple edge of the protoplasm.Osmosis studies (orange boxes in Figure ) had an ambiguous relationship with the early understanding of cell membranes. From the earliest studies, water movement across semipermeable membranes was explicitly related to the volume changes of the cell. Osmosis can hardly be understood without the concept of membrane semipermeability and, as a result, osmotic studies have been relevant to theoretically acknowledge the cell membranes as selective barriers. Nevertheless, the first studies using artificial membranes were difficult to compare to the complexity of natural cell membranes and the analogy between the two types of membranes remained obscure for a long time.In 1748, while he was trying to preserve some alcohol from the exposition to air, Nollet immersed a vial full of ethanol in a water container and covered it with a bladder membrane. After some hours, the bladder membrane had significantly swelled. Confronted to this observation, he carried out the opposite experiment. He put the water in the vial covered with the bladder membrane and the alcohol in th the membrane sank. He concluded that the bladder membrane was permeable to water but not to ethanol []. Some years later, Hewson reported what could be considered as the first osmotic observations on living cells: He studied the shape of erythrocytes and noticed that these cells shrank or swelled depending on the salt concentration of the medium []. Although inspiring, these first reports went mostly unnoticed at first.The importance of osmosis was not entirely recognized until Dutrochet’s work between 1826 and 1838. Dutrochet rediscovered the osmosis phenomena and carried out many experiments using different solutions and membranes that settled both the physical description of the phenomena and their physiological relevance. From his early works using animal membranes, he concluded that water moved from the compartment where the solutions were the less dense, acidic or positively charged to the compartment where the substances were more dense, alkaline or negatively charged []. He was influenced by previous work by Porret, who showed that an otherwise impermeable animal membrane could become water-permeable when an electric current was applied []. Dutrochet repeated Porret’s experiments and first thought that the water movement across the membrane could be somehow related to electricity []. His contemporaries also suggested that capillarity or viscosity differences between the solutions may account for the observed phenomena [],[]. However, a more systematic analysis allowed Dutrochet to discard all these hypotheses, including his own []. He concluded that the reason for the water movement was the heterogeneity of the liquids in the two compartments, but the underlying nature of the heterogeneity remained unknown to him []. It may be surprising to notice how hard it was for Dutrochet to explain the phenomena that he observed, but this has to be considered in its context: Diffusion was qualitatively described by Graham in the 1830s and Fick did not provide his quantitative equations for diffusion until 1855 [],[].From the beginning of his experiments, Dutrochet extended his observations on osmosis to physiology []. He explained plant turgescence by the fact that plant cells used osmosis to accumulate water. His work on osmosis certainly influenced his opinion that cells were surrounded by essential cell membranes, though his way of describing them looks alien to us today. He suggested that cell borders acted as “chemical sieves”, which we would now describe as semipermeable, although he did not use that term. The chemical sieve-membrane would have been able to change the composition of the cell medium, resulting in the “secretion” (~metabolism) of substances to both the exterior and the interior of the cell [].In 1844, Von Mohl treated plant tissues with alcohol and different acids and described the detachment of the protoplasm from the interior of the cell walls. He named the shrinking vesicle that separated from the cell walls the “primordial utricule” [],[]-[]. In addition to this chemical method, in the 1850s N?geli and other authors put plant cells in hypertonic media and observed the contraction of a vesicle within the cell walls [],[],[]-[]. Over time, such osmotic studies became more quantitative, and by 1884, De Vries and Hamburguer among other authors were able to use plant and animal cell models to show that, except for electrolytes, most solutions applied equal osmotic pressures at equal concentrations [],[].Although today these results may seem quite straightforward to analyze, at their time they were not decisive because the membranes remained invisible. It is unclear if Von Mohl thought that the primordial utricule was surrounded by an envelope or was a naked portion of protoplasm []. N?geli believed that the semipermeable membrane resulted from the hardening of the exterior layer of protoplasm in contact with water, thus supporting the idea that membranes were not different from the rest of the cell []. Jacobs has argued that, even after their detailed osmotic studies, de Vries and Hamburguer did not assume that cells were necessarily bounded by membranes []; de Vries was actually aware of the fact that the osmotic phenomena he was measuring reflected volume changes in the massive plant vacuole, thus diverting the attention from membranes [],[]. Finally, the opponents to cell membranes were comforted by N?geli’s experiments on the idea that the naked protoplasm was the active component of the cell, whereas the rigid cell wall was an unessential secondary element that could even be removed from the cell [].Two concepts are important here to understand how the cell was portrayed in the late XIXth century and early XXth century: the colloid and the precipitation membranes (red boxes in Figure ). In 1861, Graham separated the water-soluble molecules into two sorts according to their ability to cross a parchment paper: Inorganic salts and sugars easily crossed the membrane and were called crystalloids, whereas gelatin-like compounds were unable to do so and were named colloids []. Biologists rapidly adopted the term “colloid” to refer to the structure of the protoplasm, probably because it seemed more precise in describing the viscous jelly-like interior of the cell. The open question then was to determine if the surface of the cell was made up of the same substance as the rest of the protoplasm. A possible answer to that question was provided by studies on precipitation membranes.Precipitation membranes were the first artificial membranes to be synthesized. They were first developed by Traube in 1867 and so named because they were obtained by the precipitation of molecules at the interface between one solution of potassium ferrocyanide and another of copper sulfate [],[]. These membranes were permeable to water but not to other molecules, thus becoming important tools for osmotic studies. For instance, Pfeffer was able to produce sturdier precipitation membranes in 1877 and carried out several experiments that established the correlation between the osmotic pressure and the solution concentration and temperature [],[]. Precipitation membranes were highly influential in the debate about the existence of cell membranes because most authors, including those working on osmosis, assimilated the cell membranes to a precipitation membrane. According to that point of view, the protoplasmic colloid precipitated when it was in contact with the aqueous medium, but this did not require the membrane to be any different from the rest of the protoplasm (Figure ).
Figure 5 XIX
th century doubts about the existence of membranes. A. In this vision, the cell is devoid of any membrane and all the properties of the cell are defined by the activity of the protoplasmic colloid. B. The cell is surrounded by an external layer (membrane) of which the nature is distinct to the rest of the protoplasm. Yet, in this view, the inside of the cell remains a colloid. To summarize, despite the important developments in osmosis that were taking place during the second half of the XIXth century and the intrinsic necessity of membranes to explain this phenomenon, it would be misleading to think that cell membranes were considered mandatory cell structures at the time. Even those who acknowledged the fact that osmosis requires semipermeable membranes to take place, envisioned cell borders as precipitation membranes at the surface of a protoplasmic colloid–a point of view irreconcilable with our current understanding of cells.As it has been shown so far, during most of the XIXth century, cell membranes attracted limited attention and the dominant opinion was that cell membranes (often mistaken for cell walls) were secondary structures that resulted from the contact between the protoplasmic colloid and the environment. This vision of things changed at the turn of the XXth century but marginally remained until well into that century. In this regard, Fischer’s work in 1921 is noteworthy because he called into question the concept of cell membranes at a time when their existence was generally taken for granted but direct evidence remained scarce. His arguments, which can be considered as the culmination of the XIXth century point of view on membranes, were the following []: 1) Cell membranes were invisible usin even when the edge of the cell was visible, it did not prove the existence of membranes with characteristics different from the re 2) When cells were immersed in a hypertonic medium, they shrank less than would be expected from str 3) Cell permeability to different molecules seemed to change depending on many factors—an observation seemingly incompatible with contemporary descriptions of the membrane as sieves or a 4) Fischer claimed that cell fragments behaved similarly with solutes than whole cells, although he did not provide a precise account of the experiments
and 5) Since he assumed that the interior of the cell was a colloid, he argued that cell membrane models still had to explain how the molecules moved within the colloid (the cell) once they had crossed the membrane. As a result of all these criticisms, he concluded that the external layer of the protoplasm could only be conceived as a “surface tension film” made up of the same compounds as the protoplasm and lacking any osmotic value.Fischer’s opinions were certainly not dominant at the time, but the colloid hypothesis did not die out until progress in enzymology and molecular biology replaced the homogeneous, gelatin-like description of the protoplasm by studying discrete compounds of life. The existence of membranes was vindicated as late as the 1950s and there are even some authors who still call it into question [],[].The existence of cell membranes did not become popular until the turn of the XXth century. In this section I will present the different pieces of evidence that led to the general acknowledgement of the existence of cell membranes in its modern sense.In the 1890s, two confronting views competed each other to explain how semipermeable membranes operated: Traube had suggested that precipitation membranes had small pores that allowed them to behave like sieves, whereas Nernst introduced the idea that permeating substances were those that could dissolve in the membranes [],[],[]. From 1895 to 1899, Overton carried out a series of experiments in which he immersed cells in solutions of over 500 different substances at the same concentration in order to study their permeability with different molecules []-[]. He noticed that solutions of ether-soluble (apolar) molecules did not result in the shrinking of cells, contrary to solutions of water-soluble (polar) substances. He concluded that apolar molecules entered the cells with less difficulty than polar substances, and he showed that this was irrespective of their molecular size. Since solubility, not molecular size, was the best predictor of the entry of substances in the cell, Overton favored Nernst’s hypothesis for membrane permeability []. Based on the observation that not all molecules could enter the cells with the same ease, but also aware that the cellulose cell wall could not be involved in the phenomenon, he suggested that there was a cell membrane distinct from the cellulose cell wall [],[] and that these cell membranes were made up of ether-soluble components [],[]. Looking for specific polar candidates that could make up the membranes, he ruled out the triglycerides because they would be subject to saponification in the regular living conditions of cells. He suggested that cholesterol and phospholipids could be the main components of cell membranes even though little was known at the time about the cellular functions of these molecules. He also recognized the difficulty that the membrane solubility theory may introduce in explaining the movement of water and other hydrophilic substances across the cell boundaries. He tried to solve this paradox by recalling that, in spite of their hydrophobic nature, cholesterol esters and cholesterol-lecithin mixtures were known to absorb large water volumes []. He also suggested that some kind of active property of the protoplasm could allow the active transport of molecules into the cell [],[]. Similar, lesser-known observations were also reported in bacteria and analyzed in a similar way [],[]. Yet, Overton remained the authoritative figure to which most future cell membrane works would refer (dark green boxes in Figure ).In 1855, N?geli had already made some interesting observations about the permeability of dyes in the plant cell [],[]. First, he noticed that when plant vacuoles were filled with a pigmented solution, the osmotic changes could modify the volume of the vacuole but the pigment did not leak outside the vacuole unless it was artificially damaged. He also showed that when plant cells were immersed in hypertonic colored solutions, the protoplasm shrank and the colored solutions could be observed in the space between the protoplasm and the cell wall, but the pigments did not enter the protoplasm. As a result of both observations, he concluded that the vacuole boundaries and the protoplasmic surface were barriers to penetration [],[]. Still, as we have seen previously, N?geli did not think that the cell was bounded by a differentiated membrane so he assumed that the resistance to pigmentation was a general characteristic of the whole protoplasm rather than the consequence of the activity from a specific part of the cell. Overton revived the interest for dyes and, in accordance with his previous work, visually confirmed that lipid-soluble dyes entered the cells more easily than water-soluble dyes [],[]. Yet, these observations did not definitively prove that cell membranes were chemically different from the rest of the protoplasm. It was not until 1922 that the improvement in the microinjection techniques provided a crucial answer to this issue. Chambers used this technique to apply a water-soluble cytolysogenic (i.e. able to digest the cytoplasm) solution in different parts of the cell. He showed that he could apply the hydrophilic cytolysogenic substance on the surface of starfish eggs without damaging them. Then, he injected a small amount in the interior of the cell and he observed the cytolysis of the protoplasm. When the injection was made close to the cell borders, the cytolysis spread in the protoplasm but did not impact the membrane until the rest of the cell had been massively damaged []. This was the first unavoidable evidence that the nature of the cell surface was different from the rest of the protoplasm, supporting the existence of the cell membrane.The electrophysiology is a domain unto itself, so here I will only briefly summarize the main indirect contributions to the field of cell membranes at the turn of the XXth century (purple boxes in Figure ). There are two components in this story. The first is the primal electrophysiology debate incarnated in the opposition between du Bois-Reymond and Hermann []: In 1848, the former had reported an electric current and action potential in muscles and nerves and tried to explain them by the preexisting charge differences between the interior and the exterior of the tissues [],[]; In 1867, the latter assumed that the currents measured by du Bois-Reymond were an artifact and that the electrolytes found in the external medium resulted from the chemical decomposition of the samples [],[]. The second element of this story is the field of electrochemistry, which was emerging very fast thanks to the development of more precise mathematical models. It began when de Vries attracted Von’t Hoff’s attention to the problem of osmotic pressure. Von’t Hoff first used the osmotic measurements from Pfeffer, De Vries, Hamburguer, Donders and Raoult to suggest the theoretical and experimental equivalence between the laws of ideal gases and those that ruled the behavior of dilute solutions [],[]. The main exception that did not seem to fit into Von’t Hoff’s hypothesis were electrolytes. Arrhenius contacted Von’t Hoff in a personal communication and put him on the track to explain the observed anomalies based on the dissociation hypothesis. Eventually, Nernst, who was studying the relationship between electricity and electrolyte movements, developed Von’t Hoff’s equations for the calculation of the electric potential and electromotive force in galvanic cells [],[].These two lines of research met through Bernstein’s work in 1902. Bernstein used a physiological model to corroborate some of the electrochemical predictions made by Nernst. In particular, he showed that temperature changes impacted the electromotive forces in muscles according to Nernst’s predictions [],[]. The reconciliation of electrophysiology with electrochemistry allowed Bernstein to formulate the “membrane theory of electrical potentials”. Bernstein’s membrane theory postulated that (1) nerves consisted of a conducting electrolyte bounded by thin membranes (2) in the resting state, the membrane kept an electric potential with internal negative charges and exter and (3) in the activity period, potassium permeability increased and the electric potential consequently dropped [],[].In the 1910s, H?ber carried out a series of experiments that corroborated Bernstein’s theory and coincidentally provided supplementary evidence in favor of the existence of cell membranes. H?ber showed that conductivities of muscle or compacted erythrocytes were higher at high electrical frequencies than at low frequencies. He suggested that membranes were impermeable at low electrical frequencies but became less resistant at high frequencies because the cells themselves were disrupted. In order to test this hypothesis, H?ber measured the internal conductivity of the cells. The values that he obtained were not compatible with the attachment of electrolytes to the protoplasmic colloid, but they supported their solution in the internal medium. The corollary of these results was that the only way to prevent the electrolytes from diffusing out of the cell was to present an impermeable boundary with properties different from the rest of the protoplasm []-[].In short, in the early XXth century the presence of membranes was becoming widely accepted and was supported by three lines of evidence: Overton’s permeability studies, Chamber’s microinjection experiments and H?ber’s electrical measures. Nonetheless, it should be noted that for some organisms, especially bacteria, this debate was not definitively closed until several decades later, when cell membranes could be directly observed using the electron microscope []-[].In the previous section, I have shown that many authors in the XIXth century thought that membranes were not essential parts of cells and even those who recognized their importance did not conceive membranes as we do today. By the turn of the XXth century, cell membranes had become a convenient assumption supported by a few direct experiments. The next decades would witness an increasing interest in describing membrane structure (dark green boxes in Figure ).In the early XXth century it appeared clear that, if cell membranes existed, they would likely be at least partially lipid-based. The opinion that the cell surface could be covered by a thin lipid layer goes back to the 1880s [],[] but it was not popularized until Overton’s publications in
(see previous section). The molecular structure of membranes remained unexplored until the major breakthrough made by Gorter and Grendel in 1925.The genius of this paper was to compare the surface that cell lipids were able to occupy to the total surface of cells. Gorter and Grendel extracted the lipids from a since these cells were known to lack internal membranes, they assumed that all lipids should come from the cell envelopes. Measuring the spread of lipids on water was done using a Langmuir’s trough (Figure ). This device had first been developed by Pockels as a way to precisely measure the surface covered by lipid monolayers at the interface between water and air [], but it was named after Langmuir’s version more than 25 years later []. When Gorter and Grendel compared the surface covered by the lipids to the estimated sum of cell surfaces, they found a 2:1 ratio (Figure ). As a result, they concluded that cells were surrounded by a lipid membrane two molecules thick–a lipid bilayer–with the hydrophobic components in the internal part of the membrane and the hydrophilic components in the external part [].
Figure 6 Oil at air/water interfaces. A. Oil molecules spontaneously spread on the air/water interface until they form a layer one molecule thick. B. The Langmuir trough allows to precisely measure the surface that these monolayers can spread depending on the applied pressure.
Figure 7 Surface measurement of membrane lipid monolayers as a way to determine membrane structure. A. Summary of the method, consisting in the comparison between the surface occupied by lipids extracted from membranes and the estimated surface of cells B. Different results and interpretations. This study has been commonly cited as the most conclusive argument in favor of the lipid bilayer nature of cell membranes. In spite of the elegance of this work, it is important to balance its contribution to the field because it is subject to criticisms from both technical and theoretical grounds. First, the extraction technique employed could not isolate the totality of erythrocyte lipids from the samples []. In addition, the equation that Gorter and Grendel used to estimate the surface of the erythrocytes also underestimated the cell area []. Some historical reviews on membrane discovery have argued that it was fortunate that the two errors neutralized each other in order to give credit to the lipid bilayer hypothesis that we now recognize in current membrane models []. But it should be recalled that the lipid bilayer hypothesis of 1925 did not leave room for anything else than lipids to be located in the membrane plane–in contrast to past and current mosaic hypotheses. Some parallel reports even contradicted Gorter and Grendel’s values (Figure ). Dervichian and Macheboeuf carried out a similar analysis and obtained a 1:1 as a result, they assumed that the cell membrane was a lipid monolayer []. Although this second work also had lipid extraction problems, the major difference between the two studies was that Gorter and Grendel measured the surface covered by lipids at the first detected pressure (i.e. the maximal continuous surface covered by an amount of lipid) whereas Dervichian and Machebouef measured the surface right before the collapse pressure (i.e. the minimal surface before the monolayer collapsed). In the 1960s, a more accurate ratio for the lipid surface at the collapse pressure with respect to the cell surface estimates was calculated to be 1,3:1 []; the authors of this later study suggested that their ratio conformed to loose lipid bilayers, whereas the modern interpretation of the fluid mosaic model supports the idea that membrane lipids are tightly packed and the “excess space” is actually occupied by membrane proteins.Apart from the technical issues, it is worth noting the theoretical bases on which Gorter and Grendel founded their lipid bilayer concept. Some years earlier, in the 1910s, some pioneer papers had studied the behavior of amphiphilic molecules at the interface between water and air [],[],[]. For instance, in 1917 Langmuir used the valence bond theory suggested by Lewis the previous year [] to explain molecular hydrophily on the grounds of “secondary valence”, i.e. chemical polarity []. Langmuir put forward this hypothesis in the same paper in which he presented the trough that, somewhat unfairly, was named after him. Notwithstanding, Gorter and Grendel only cited Langmuir’s paper in a very superficial way related to the trough []. Instead of reasoning in terms of hydrophily and hydrophobicity, they suggested the bilayer structure based on crystallographic studies [] and soap bubble observations, which were only distantly related to their subject []. Gorter and Grendel are not really to blame because hydrophobic interactions were very poorly understood at the time. Subsequent authors, like Danielli, discussed the importance of the amphipathic nature of lipids and proteins to account for their respective structural hypotheses, but they disregarded the importance of hydrophobic interactions []. Even Langmuir, who extended his explanation of amphipatic molecules to protein monolayers [], overlooked the hydrophobic interactions between proteins and lipids [] when he came to envision the cell membrane.In summary, although Gorter and Grendel’s work was decisive for making the lipid bilayer concept popular in 1925, its actual contribution to current membrane models can only be appreciated in the light of later progress in membrane studies and hydrophobic interaction understanding [].The formulation of the lipid bilayer hypothesis had opened the door to the molecular description of cell membrane structure. In an attempt to confirm or refute the lipid bilayer postulate, one of the first lines of research to be explored was the measurement of membrane thickness. The first attempt to estimate the thickness of cell membranes was directly related to H?ber’s research on cell conductivity (see above). In 1925, Fricke measured the static capacitance per surface unit with an estimation of the cell membrane dielectric constant. He extrapolated that the thickness of erythrocyte and yeast cell membranes was in a range between 3.3 and 4 nm [],[]. This thickness was compatible with a lipid monolayer but not with a bilayer, thus providing support to the monolayer membrane proponents []. The choice of the dielectric constant used in these studies was called into question but the subsequent tests could not refute the estimation by Fricke []. Independently, the leptoscope was invented in order to measure very thin membranes by comparing the intensity of light reflected from a sample to the intensity of a membrane standard of known thickness []. This device measured thicknesses that depended on pH and the presence of membrane proteins and ranged from 8.6 to 23.2 nm. As a result, the lower values supported the lipid bilayer hypothesis whereas the higher ones could support the presence of supplementary superimposed layers []. The thickness of the membrane would only become really accessible two decades later, when the observation of membrane sections using electron microscopy established the now accepted ~8 nm value for standard cell membranes [].The 1930s were important in this field because the decade introduced the most influential membrane structure model until the general agreement on the fluid mosaic model, namely the paucimolecular model (Figure ). The genesis of this model relied on studies of surface tension between oils and echinoderm/teleostei eggs []-[]. As the surface tension values appeared to be much lower than would be expected for an oil–water interface, it was assumed that some substance was responsible for lowering the interfacial tensions in the surface of cells []. At this time, membranes were known to contain substantial quantities of proteins [],[] but little had been said about their position in cell membranes. Therefore, in 1935 Danielli and Davson suggested that the lipid bilayer was sandwiched between two thin protein layers []. Although the paucimolecular model was characterized by the superposition of protein and lipid layers (Figure ), the authors were aware of the contemporary debates about membrane permeability (discussed later), so they admitted the possibility that some proteins could span the membrane.
Figure 8 Membrane structure hypotheses in the 1930’s. A. Paucimolecular model, with a lipid bilayer coated with proteins in both sides. B. H?ber’s mosaic model in which membranes behaved both as solvents and sieves. The paucimolecular model immediately became popular and it dominated cell membrane studies for the following 30 years. From the beginning, it was confronted with a balance of supportive and critical observations. Among the so-called supportive evidence, there were some light polarization and X-ray diffraction studies. In order to provide insights on membrane structure, these methods required repeated structures, so the samples used were myelinized axons. These analyses showed an alternation of protein and lipid layers in support of the paucimolecular model []-[]. Unfortunately, we know now that this biological material is physiologically very specific and can hardly be compared to a regular cell membrane.The hypotheses that challenged the paucimolecular model will be further developed below, but first I will present some details regarding the aforementioned studies on surface tension. The surface tension experiments that led to the paucimolecular model used triglyceride oils and other non-miscible lipids. These substances are appreciably different from most natural amphipathic cell membrane components and, therefore, they are not suitable for a realistic comparison to cell membranes. Danielli and other authors showed soon after the postulation of the paucimolecular model that the addition of amphipatic cell membrane components like fatty acids, cholesterol or phospholipids to non-miscible mixtures was very effective in dropping the interfacial tension between water and highly hydrophobic substances [],[]. As a result, shortly after the suggestion of the paucimolecular model, the main argument that motivated it, namely the requirement of proteins to lower the superficial tension of the cell, had been dismissed. Yet, the hypothesis remained popular for 30 more years.Despite of the prevalence of the paucimolecular model in the mid-XXth century, this hypothesis was not devoid of competitors. Direct experiments on cell surfaces were scarce but permeability studies provided an outstanding playground for indirect speculations about cell membrane structure. Permeation studies suggested what would to be called the “mosaic models”.As it was previously pointed out, Overton’s hypothesis that apolar molecules easily entered the cell because they could get dissolved in the cell lipid membranes automatically raised the problem of how polar molecules accessed it. In an attempt to circumvent this issue, Nathansohn suggested in 1904 that the cell surface could be a mosaic combining fat-like parts with protoplasmic-like parts [],[]. In the early XXth century, the “mosaic” term was recycled to refer to membranes with heterogeneous parts []-[]. In the 1930s H?ber amended it to fit the idea that membranes were a mixture of sieve-like and solvent (i.e. lipid) parts []-[]. These mosaic hypotheses were the result of the combination of the two classic ways of understanding the permeation through membranes: Traube’s precipitation membranes and Nernst/Overton lipid membranes. In the first case the molecular and pore sizes were predicted to best account fo in the second, the hydrophobicity was the best predictor of molecular permeability. The compromise reached described the cell membranes as lipid layers interrupted by pores (Figure , []). Since the permeability of some polar molecules had been shown to change according to different conditions [],[], it was also suggested that the pore diameter could change according to the hydration of the pore, the pH, its obstruction by some particular molecule, the membrane stretching, the metabolic activity and the cell type []. Most descriptions did not specify the type of molecules that could form these pores, but proteins were among the best candidates [],[].Apart from the mosaic hypotheses proponents, other authors also called into question the paucimolecular model. For example, in their presentation to the very influential 1940 symposium on the permeability of cell membranes, Parpart and Dziemian reported the chemical composition that could be analyzed from cell extracts []. Although these authors did not specifically support the mosaic models, they noted that lipases in contact with cells modified the cell permeability, which suggested that surface phospholipids were naked instead of coated with proteins. The discussion that followed their talk is remarkable because several authors exposed their visions for membrane protein structure: Ponder imagined the proteins adopted a spaghetti-like shape on top of the membrane whereas Davson suggested that proteins could span the whole erythrocyte, not just the membrane.In 1936, Danielli, who was probably the most influential author in the field at the time, discussed a complete catalog of possible membrane structures in addition to his paucimolecular model []. He excluded all membrane models that were much thicker than 8 nm because he thought it was the most plausible cell membrane thickness. He classified the membrane models in three types: continuous lipid membranes, mosaic membranes and lipo-protein membranes (Figure ). In the first type, he imagined all the possible combinations of lipid monolayers and bilayers coated with proteins. He concluded that a lipid bilayer with the polar parts of the lipids in the exterior would be the most stable structure because it maximized the contact of the hydrophilic lipid parts with water. He assumed that the proteins were subject to the same amphipatic constraints as lipids but in their own layers. In the mosaic-like models, he considered different distributions of proteins and lipids, but he ruled all of them out because he assumed that lateral interactions between lipid hydrophobic parts and proteins would not have been stable. He also considered that if the lipid bilayer had not been covered by proteins, it would not have been solid enough to provide a reliable impermeable barrier to resist to cell deformation. Finally, he did not go into the detail of the lipoprotein membranes because little was known about such kind of molecules. Concerning ion permeability, he acknowledged the three popular possibilities of his time: pores, simple diffusion and the existence of some kind of transporter in the membrane [].
Figure 9 Possible molecular arrangements of biological membranes redrawn from Danielli in 1936 [ []] . A-E. Cross-section of hypothetical membranes with internal lipids and coating proteins. F. Cross-section of an hypothetical membrane made up of lipoprotein subunits. G-I. Surface of mosaic membranes. In summary, many hypotheses on cell membrane structure were under discussion in the late 1930s. Among these, the paucimolecular and the mosaic models were certainly the most iconic. The next developments would be highly influenced by the evidence from independent, though membrane-related, fields.The direct characterization of membrane structure did not progress much until new techniques allowed dramatic discoveries in the late 1950s and 1960s. Before these new methods became available, cell membranes attracted the attention from authors who were studying membrane roles in physiology and metabolism. Although these contributions were not always immediately recognized by the community working on membrane studies, it is important to take them into account because they illustrate how works of this period (s) indirectly changed membrane understanding.Most of the studies presented in this section are related to molecular transport across membranes and did not directly address the question of membrane structure. Therefore, I will not go into detail for discoveries in these fields but I will just provide some general clues to illustrate how the contextual research impacted cell membrane conceptions. For more complete accounts on the history of transpor