¹ 10. The cell - the principal part of the organism. Tissues of the human body. 

Adjectives. The Degrees of comparison of adjectives. Numerals. Cardinal and ordinal numerals.

 

Cell

Drawing of the structure of cork as it appeared under the microscope to Robert Hook from Micrographia which is the origin of the word "cell".

Drawing of the structure of cork as it appeared under the microscope to Robert Hook from Micrographia which is the origin of the word "cell".

Cells in culture, stained for keratin (red) and DNA (green).

Cells in culture, stained for keratin (red) and DNA (green).

The cell is the structural and functional unit of all living organisms, and is sometimes called the "building block of life." Some organisms, such as bacteria, are unicellular (consist of a single cell). Other organisms, such as humans, are multicellular. (Humans have an estimated 100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 nanogram.) The largest known cell is an ostrich egg.

The cell theory, first developed in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed of one or more cells. All cells come from preexisting cells. Vital functions of an organism occur within cells, and all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.

The word cell comes from the Latin cellula, a small room. The name was chosen by Robert Hooke when he compared the cork cells he saw to the small rooms monks lived in.

Overview

Each cell is at least somewhat self-contained and self-maintaining: it can take in nutrients, convert these nutrients into energy, carry out specialized functions, and reproduce as necessary. Each cell stores its own set of instructions for carrying out each of these activities.

Mouse cells grown in a culture dish. These cells grow in large clumps, but each individual cell is about 10 micrometres across.

Mouse cells grown in a culture dish. These cells grow in large clumps, but each individual cell is about 10 micrometres across.

All cells share several abilities:

·                     Reproduction by cell division (binary fission, mitosis or meiosis).

·                     Use of enzymes and other proteins coded for by DNA genes and made via messenger RNA intermediates and ribosomes.

·                     Metabolism, including taking in raw materials, building cell components, converting energy, molecules and releasing by-products. The functioning of a cell depends upon its ability to extract and use chemical energy stored in organic molecules. This energy is derived from metabolic pathways.

·                     Response to external and internal stimuli such as changes in temperature, pH or nutrient levels.

·                     Cell contents are contained within a cell surface membrane that contains proteins and a lipid bilayer.

Some prokaryotic cells contain important internal membrane-bound compartments, but eukaryotic cells have a highly specialized endomembrane system characterized by regulated traffic and transport of vesicles.

Anatomy of cells

There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually singletons, while eukaryotic cells are usually found in multicellular organisms.

Prokaryotic cells

Diagram of a typical prokaryotic cell

Diagram of a typical prokaryotic cell

Prokaryotes are distinguished from eukaryotes on the basis of nuclear organization, specifically their lack of a nuclear membrane. Prokaryotes also lack most of the intracellular organelles and structures that are characteristic of eukaryotic cells (an important exception is the ribosomes, which are present in both prokaryotic and eukaryotic cells). Most functions of organelles, such as mitochondria, chloroplasts, and the Golgi apparatus, are taken over by the prokaryotic plasma membrane. Prokaryotic cells have three architectural regions: appendages called flagella and pili — proteins attached to the cell surface; a cell envelope consisting of a capsule, a cell wall, and a plasma membrane; and a cytoplasmic region that contains the cell genome (DNA) and ribosomes and various sorts of inclusions. Other differences include:

·                     The plasma membrane (a phospholipid bilayer) separates the interior of the cell from its environment and serves as a filter and communications beacon.

·                     Most prokaryotes have a cell wall (some exceptions are Mycoplasma (a bacterium) and Thermoplasma (an archaeon)). It consists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents the cell from "exploding" (cytolysis) from osmotic pressure against a hypotonic environment. A cell wall is also present in some eukaryotes like plants (cellulose) and fungi, but has a different chemical composition.

·                     A prokaryotic chromosome is usually a circular molecule (an exception is that of the bacterium Borrelia burgdorferi, which causes Lyme disease). Even without a real nucleus, the DNA is condensed in a nucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular. Plasmids can carry additional functions, such as antibiotic resistance.

Eukaryotic cells

Diagram of a typical eukaryotic cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11) cytoplasm (12) lysosome (13) centrioles

Diagram of a typical eukaryotic cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11) cytoplasm (12) lysosome (13) centrioles

Eukaryotic cells are about 10 times the size of a typical prokaryote and can be as much as 1000 times greater in volume. The major difference between prokaryotes and eukaryotes is that eukaryotic cells contain membrane-bound compartments in which specific metabolic activities take place. Most important among these is the presence of a cell nucleus, a membrane-delineated compartment that houses the eukaryotic cell's DNA. It is this nucleus that gives the eukaryote its name, which means "true nucleus". Other differences include:

·                     The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls may or may not be present.

·                     The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by a membrane. Some eukaryotic organelles also contain some DNA.

·                     Eukaryotes can move using cilia or flagella. The flagella are more complex than those of prokaryotes.

Table 1: Comparison of features of prokaryotic and eukaryotic cells

 

Prokaryotes

Eukaryotes

Typical organisms

bacteria, archaea

protists, fungi, plants, animals

Typical size

~ 1-10 µm

~ 10-100 µm (sperm cells, apart from the tail, are smaller)

Type of nucleus

nucleoid region; no real nucleus

real nucleus with double membrane

DNA

circular (usually)

linear molecules (chromosomes) with histone proteins

RNA-/protein-synthesis

coupled in cytoplasm

RNA-synthesis inside the nucleus
protein synthesis in cytoplasm

Ribosomes

50S+30S

60S+40S

Cytoplasmatic structure

very few structures

highly structured by endomembranes and a cytoskeleton

Cell movement

flagella made of flagellin

flagella and cilia made of tubulin

Mitochondria

none

one to several dozen (though some lack mitochondria)

Chloroplasts

none

in algae and plants

Organization

usually single cells

single cells, colonies, higher multicellular organisms with specialized cells

Cell division

Binary fission (simple division)

Mitosis (fission or budding)
Meiosis

 

Table 2: Comparison of structures between animal and plant cells

 

Typical animal cell

Typical plant cell

Organelles

·                     Nucleus

o                     Nucleolus (within nucleus)

·                     Rough endoplasmic reticulum (ER)

·                     Smooth ER

·                     Ribosomes

·                     Cytoskeleton

·                     Golgi apparatus

·                     Cytoplasm

·                     Mitochondria

·                     Vesicles

·                     Lysosomes

·                     Centrosome

o                     Centrioles

o                     Vacuoles

·                     Nucleus

o                     Nucleolus (within nucleus)

·                     Rough ER

·                     Smooth ER

·                     Ribosomes

·                     Cytoskeleton

·                     Golgi apparatus (dictiosomes)

·                     Cytoplasm

·                     Mitochondria

·                     Vesicles

·                     Chloroplast and other plastids

o                     Central vacuole(large)

o                     Tonoplast (central vacuole membrane)

·                     Peroxisome

·                     Vacuoles

·                     Glyoxysome

Additional structures

·                     Plasma membrane

·                     Flagellum

·                     Cilium

·                     Plasma membrane

·                     Flagellum (only in gametes)

·                     Cell wall

·                     Plasmodesmata

Subcellular components

The cells of eukaryotes (left) and prokaryotes (right).

The cells of eukaryotes (left) and prokaryotes (right).

All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates its interior from its environment, regulates what moves in and out (selectively permeable), and maintains the electric potential of the cell. Inside the membrane, a salty cytoplasm takes up most of the cell volume. All cells possess DNA, the hereditary material of genes, and RNA, containing the information necessary to build various proteins such as enzymes, the cell's primary machinery. There are also other kinds of biomolecules in cells. This article will list these primary components of the cell, then briefly describe their function.

Cell membrane: A cell's defining boundary

The cytoplasm of a cell is surrounded by a plasma membrane. The plasma membrane in plants and prokaryotes is usually covered by a cell wall. This membrane serves to separate and protect a cell from its surrounding environment and is made mostly from a double layer of lipids (hydrophobic fat-like molecules) and hydrophilic phosphorus molecules. Hence, the layer is called a phospholipid bilayer. It may also be called a fluid mosaic membrane. Embedded within this membrane is a variety of protein molecules that act as channels and pumps that move different molecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can either let a substance (molecule or ion) pass through freely, pass through to a limited extent or not pass through at all. Cell surface membranes also contain receptor proteins that allow cells to detect external signalling molecules such as hormones.

Cytoskeleton: A cell's scaffold

The cytoskeleton acts to organize and maintain the cell's shape; anchors organelles in place; helps during endocytosis, the uptake of external materials by a cell, and cytokinesis, the separation of daughter cells after cell division; and moves parts of the cell in processes of growth and mobility. The eukaryotic cytoskeleton is composed of microfilaments, intermediate filaments and microtubules. There is a great number of proteins associated with them, each controlling a cell's structure by directing, bundling, and aligning filaments. The prokaryotic cytoskeleton is less well-studied but is involved in the maintenance of cell shape, polarity and cytokinesis.

Genetic material

Two different kinds of genetic material exist: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Most organisms use DNA for their long-term information storage, but some viruses (e.g., retroviruses) have RNA as their genetic material. The biological information contained in an organism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g., mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic code itself.

Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial chromosome) in the nucleoid region of the cytoplasm. Eukaryotic genetic material is divided into different, linear molecules called chromosomes inside a discrete nucleus, usually with additional genetic material in some organelles like mitochondria and chloroplasts (see endosymbiotic theory).

A human cell has genetic material in the nucleus (the nuclear genome) and in the mitochondria (the mitochondrial genome). In humans the nuclear genome is divided into 46 linear DNA molecules called chromosomes. The mitochondrial genome is a circular DNA molecule separate from the nuclear DNA. Although the mitochondrial genome is very small, it codes for some important proteins.

Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a process called transfection. This can be transient, if the DNA is not inserted into the cell's genome, or stable, if it is.

Organelles

The human body contains many different organs, such as the heart, lung, and kidney, with each organ performing a different function. Cells also have a set of "little organs," called organelles, that are adapted and/or specialized for carrying out one or more vital functions. Membrane-bound organelles are found only in eukaryotes.

 

Diagram of a cell nucleus

 

Cell nucleus (a cell's information center) 

The cell nucleus is the most conspicuous organelle found in a eukaryotic cell. It houses the cell's chromosomes, and is the place where almost all DNA replication and RNA synthesis occur. The nucleus is spherical in shape and separated from the cytoplasm by a double membrane called the nuclear envelope. The nuclear envelope isolates and protects a cell's DNA from various molecules that could accidentally damage its structure or interfere with its processing. During processing, DNA is transcribed, or copied into a special RNA, called mRNA. This mRNA is then transported out of the nucleus, where it is translated into a specific protein molecule. In prokaryotes, DNA processing takes place in the cytoplasm.

 

Mitochondria and Chloroplasts (the power generators) 

Mitochondria are self-replicating organelles that occur in various numbers, shapes, and sizes in the cytoplasm of all eukaryotic cells. As mitochondria contain their own genome that is separate and distinct from the nuclear genome of a cell, they play a critical role in generating energy in the eukaryotic cell, they give the cell energy by the process of respiration, adding oxygen to food (typicially pertaining to glucose and ATP) to release energy. Organelles that are modified chloroplasts; they are broadly called plastids, and are often involved in storage. Since they contain their own genome, they are thought to have once been separate organisms, which later formed a symbiotic relationship with the cells. Chloroplasts are the counter-part of the mitochondria. Instead of giving off CO2 and H2O Plants give off glucose, oxygen, 6 molecules of water (compaired to 12 in respiration) this process is called photosynthesis.

 

Diagram of an endomembrane system

 

 

Endoplasmic reticulum and Golgi apparatus (macromolecule managers) 

The endoplasmic reticulum (ER) is the transport network for molecules targeted for certain modifications and specific destinations, as compared to molecules that will float freely in the cytoplasm. The ER has two forms: the rough ER, which has ribosomes on its surface, and the smooth ER, which lacks them. Also the Golgi apparatus's ends "pinch" off and become new vacuoles in the animal cell.

 

Ribosomes (the protein production centers in the cell) 

The ribosome is a large complex, composed of many molecules, in prokaryotes only exist floating freely in the cytosol, whereas in eukaryotes they can be found either free or bound to membranes.

Lysosomes and Peroxisomes (of the eukaryotic cell) 

The cell could not house such destructive enzymes if they were not contained in a membrane-bound system. These organelles are often called a "suicide bag" because of their ability to detonate and destroy the cell.

Centrosome (the cytoskeleton organiser) 

The centrosome produces the microtubules of a cell - a key component of the cytoskeleton. It directs the transport through the ER and the Golgi apparatus. Centrosomes are composed of two centrioles, which separate during cell division and help in the formation of the mitotic spindle. A single centrosome is present in the animal cells. They are also found in some fungi and algae cells.

Vacuoles 

Vacuoles store food and waste. Some vacuoles store extra water. They are often described as liquid filled space and are surrounded by a membrane. Some cells, most notably Amoeba have contractile vacuoles, which are able to pump water out of the cell if there is too much water.

Cell functions

Cell growth and metabolism

Between successive cell divisions, cells grow through the functioning of cellular metabolism.

Cell metabolism is the process by which individual cells process nutrient molecules. Metabolism has two distinct divisions: catabolism, in which the cell breaks down complex molecules to produce energy and reducing power, and anabolism, in which the cell uses energy and reducing power to construct complex molecules and perform other biological functions. Complex sugars consumed by the organism can be broken down into a less chemically-complex sugar molecule called glucose. Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of energy, via two different pathways.

The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each reaction is designed to produce some hydrogen ions that can then be used to make energy packets (ATP). In prokaryotes, glycolysis is the only method used for converting energy.

The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and is capable of generating enough ATP to run all the cell functions.

An overview of protein synthesis.Within the nucleus of the cell (light blue), genes (DNA, dark blue) are transcribed into RNA. This RNA is then subject to post-transcriptional modification and control, resulting in a mature mRNA (red) that is then transported out of the nucleus and into the cytoplasm (peach), where it undergoes translation into a protein. mRNA is translated by ribosomes (purple) that match the three-base codons of the mRNA to the three-base anti-codons of the appropriate tRNA. Newly-synthesized proteins (black) are often further modified, such as by binding to an effector molecule (orange), to become fully active.

 

 

An overview of protein synthesis.
Within the
nucleus of the cell (light blue), genes (DNA, dark blue) are transcribed into RNA. This RNA is then subject to post-transcriptional modification and control, resulting in a mature mRNA (red) that is then transported out of the nucleus and into the cytoplasm (peach), where it undergoes translation into a protein. mRNA is translated by ribosomes (purple) that match the three-base codons of the mRNA to the three-base anti-codons of the appropriate tRNA. Newly-synthesized proteins (black) are often further modified, such as by binding to an effector molecule (orange), to become fully active.

Creation of new cells

Cell division involves a single cell (called a mother cell) dividing into two daughter cells. This leads to growth in multicellular organisms (the growth of tissue) and to procreation (vegetative reproduction) in unicellular organisms.

Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of nuclear division, called mitosis, followed by division of the cell, called cytokinesis. A diploid cell may also undergo meiosis to produce haploid cells, usually four. Haploid cells serve as gametes in multicellular organisms, fusing to form new diploid cells.

DNA replication, or the process of duplicating a cell's genome, is required every time a cell divides. Replication, like all cellular activities, requires specialized proteins for carrying out the job.

Protein synthesis

Cells are capable of synthesizing new proteins, which are essential for the modulation and maintenance of cellular activities. This process involves the formation of new protein molecules from amino acid building blocks based on information encoded in DNA/RNA. Protein synthesis generally consists of two major steps: transcription and translation.

Transcription is the process where genetic information in DNA is used to produce a complementary RNA strand. This RNA strand is then processed to give messenger RNA (mRNA), which is free to migrate through the cell. mRNA molecules bind to protein-RNA complexes called ribosomes located in the cytosol, where they are translated into polypeptide sequences. The ribosome mediates the formation of a polypeptide sequence based on the mRNA sequence. The mRNA sequence directly relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter molecules in binding pockets within the ribosome. The new polypeptide then folds into a functional three-dimensional protein molecule.

Origins of cells

The origin of cells has to do with the origin of life, and was one of the most important steps in evolution of life as we know it. The birth of the cell marked the passage from prebiotic chemistry to biological life.

Origin of the first cell

If life is viewed from the point of view of replicators, that is DNA molecules in the organism, cells satisfy two fundamental conditions: protection from the outside environment and confinement of biochemical activity. The former condition is needed to maintain the fragile DNA chains stable in a varying and sometimes aggressive environment, and may have been the main reason for which cells evolved. The latter is fundamental for the evolution of biological complexity. If freely-floating DNA molecules that code for enzymes are not enclosed into cells, the enzymes that benefit a given DNA molecule (for example, by producing nucleotides) will automatically benefit the neighbouring DNA molecules. This might be viewed as "parasitism by default." Therefore the selection pressure on DNA molecules will be much lower, since there is not a definitive advantage for the "lucky" DNA molecule that produces the better enzyme over the others: All molecules in a given neighbourhood are almost equally advantaged.

If all the DNA molecule is enclosed in a cell, then the enzymes coded from the molecule will be kept close to the DNA molecule itself. The DNA molecule will directly enjoy the benefits of the enzymes it codes, and not of others. This means other DNA molecules won't benefit from a positive mutation in a neighbouring molecule: this in turn means that positive mutations give immediate and selective advantage to the replicator bearing it, and not on others. This is thought to have been the one of the main driving force of evolution of life as we know it. (Note. This is more a metaphor given for simplicity than complete accuracy since the earliest molecules of life, probably up to the stage of cellular life, were most likely RNA molecules that acted as both replicators and enzymes: see RNA world hypothesis. However, the core of the reasoning is the same.)

Biochemically, cell-like spheroids formed by proteinoids are observed by heating amino acids with phosphoric acid as a catalyst. They bear much of the basic features provided by cell membranes. Proteinoid-based protocells enclosing RNA molecules could (but not necessarily should) have been the first cellular life forms on Earth.

Another theory holds that the turbulent shores of the ancient coastal waters may have served as a mammoth laboratory, aiding in the countless experiments necessary to bring about the first cell. Waves breaking on the shore create a delicate foam composed of bubbles. Winds sweeping across the ocean have a tendency to drive things to shore, much like driftwood collecting on the beach. It is possible that organic molecules were concentrated on the shorelines in much the same way. Shallow coastal waters also tend to be warmer, further concentrating the molecules through evaporation. While bubbles comprised of mostly water tend to burst quickly, oily bubbles happen to be much more stable, lending more time to the particular bubble to perform these crucial experiments. The Phospholipid is a good example of a common oily compound prevalent in the prebiotic seas. Phospholipids can be constructed in one's mind as a hydrophilic head on one end, and a hydrophobic tail on the other. Phospholipids also possess an important characteristic, that is having the function to link together to form a bilayer membrane. A lipid monolayer bubble can only contain oil, and is therefore not conducive to harbouring water-soluble organic molecules. On the other hand, a lipid bilayer bubble  can contain water, and was a likely precursor to the modern cell membrane. If a protein came along that increased the integrity of its parent bubble, then that bubble had an advantage, and was placed at the top of the natural selection waiting list. Primitive reproduction can be envisioned when the bubbles burst, releasing the results of the experiment into the surrounding medium. Once enough of the 'right stuff' was released into the medium, the development of the first prokaryotes, eukaryotes, and multi-cellular organisms could be achieved. This theory is expanded upon in the book, The Cell: Evolution of the First Organism by Joseph Panno Ph. D.

Origin of eukaryotic cells

The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. It is almost certain that DNA-bearing organelles like the mitochondria and the chloroplasts are what remains of ancient symbiotic oxygen-breathing bacteria and cyanobacteria, respectively, where the rest of the cell seems to be derived from an ancestral archaean prokaryote cell – a theory termed the endosymbiotic theory.

There is still considerable debate about whether organelles like the hydrogenosome predated the origin of mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.

Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant eukaryotes, may have played a role in the transition from prokaryotes to eukaryotes. An 'origin of sex as vaccination' theory suggests that the eukaryote genome accreted from prokaryan parasite genomes in numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose when infected hosts began swapping nuclearized genomes containing coevolved, vertically transmitted symbionts that conveyed protection against horizontal infection by more virulent symbionts.

 

VIDEO

Cell

 

Tissue in the human body

Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of similar cells and from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning. Organs are then formed by the functional grouping together of multiple tissues.

 

The study of tissue is known as histology or, in connection with disease, histopathology. The classical tools for studying tissues are the paraffin block in which tissue is embedded and then sectioned, the histological stain, and the optical microscope. In the last couple of decades, developments in electron microscopy, immunofluorescence, and the use of frozen tissue sections have enhanced the detail that can be observed in tissues. With these tools, the classical appearances of tissues can be examined in health and disease, enabling considerable refinement of clinical diagnosis and prognosis.

Cross section of sclerenchyma fibers in plant ground tissue

Microscopic view of a histologic specimen of human lung tissue stained with hematoxylin and eosin

Animal tissues

PAS diastase showing the fungus Histoplasma

Animal tissues can be grouped into four basic types: connective, muscle, nervous, and epithelial. Multiple tissue types comprise organs and body structures. While all animals can generally be considered to contain the four tissue types, the manifestation of these tissues can differ depending on the type of organism. For example, the origin of the cells comprising a particular tissue type may differ developmentally for different classifications of animals.

The epithelium in all animals is derived from the ectoderm and endoderm with a small contribution from the mesoderm, forming the endothelium, a specialized type of epithelium that comprises the vasculature. By contrast, a true epithelial tissue is present only in a single layer of cells held together via occluding junctions called tight junctions, to create a selectively permeable barrier. This tissue covers all organismal surfaces that come in contact with the external environment such as the skin, the airways, and the digestive tract. It serves functions of protection, secretion, and absorption, and is separated from other tissues below by a basal lamina.

Types of Tissue:

Epithelial tissue: Covering the external & internal body surfaces. e.g. – Skin, internal covering of GIT. The epithelial tissues are formed by cells that cover the organ surfaces such as the surface of the skin, the airways, the reproductive tract, and the inner lining of the digestive tract. The cells comprising an epithelial layer are linked via semi-permeable, tight junctions; hence, this tissue provides a barrier between the external environment and the organ it covers. In addition to this protective function, epithelial tissue may also be specialized to function in secretion and absorption. Epithelial tissue helps to protect organisms from microorganisms, injury, and fluid loss.

Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective absorption, protection, transcellular transport and detection of sensation. In Greek "epi" means, "on, upon," and "thele" meaning "nipple". Epithelial layers are avascular, so they must receive nourishment via diffusion of substances from the underlying connective tissue, through the basement membrane. Epithelia can also be organized into clusters of cells that function as exocrine and endocrine glands.

 

Structure

 

Cells in epithelium are very densely packed together like bricks in a wall, leaving very little intercellular space. The cells and ca form continuous sheets which are attached to each other at many locations by tight junctions and desmosomes.

 

Basement membrane

 

All epithelial cells rest on a basement membrane, which acts as a scaffolding on which epithelium can grow and regenerate after injuries. Epithelial tissue is innervated, but avascular. This epithelial tissue must be nourished by substances diffusing from the blood vessels in the underlying tissue, but they don't have their own blood supply. The basement membrane acts as a selectively permeable membrane that determines which substances will be able to enter the epithelium.

 

Cell junctions

 

Cell junctions are especially abundant in epithelial tissues. They consist of protein complexes and provide contact between neighbouring cells, between a cell and the extracellular matrix, or they build up the paracellular barrier of epithelia and control the paracellular transport.[citation needed]

 

Cell junctions are the contact points between plasma membrane and tissue cells. There are mainly 5 different types of cell junctions. They are tight junctions, adherens junctions, desmosomes, hemidesmosomes, and gap junctions. Tight junctions are a pair of trans-membranar protein fused on outer plasma membrane. Adherens junctions are a plaque (protein layer on the inside plasma membrane) which attaches both protein and microfilaments. Desmosomes attach to the microfilaments of cytoskeleton made up of keratin protein. Hemidesmosomes resemble desmosomes on a section. They are made up of the integrin (a transmembraner protein) instead of cadherin. They attach the epithelial cell to the basement membrane. Gap junctions connect the cytoplasm of two cells and are made up of proteins called connexins (six of which come together to make a connexon).

 

Classification

Types of epithelium

 

Tissues are generally classified by the morphology of their cells, and the number of layers they are composed of. Epithelial tissue that is only one cell thick is known as simple epithelium. If it is two or more cells thick, it is known as stratified epithelium. However, when taller simple epithelial cells (see columnar, below) are viewed in cross section with several nuclei appearing at different heights, they can be confused with stratified epithelia. This kind of epithelium is therefore described as "pseudostratified" epithelium.

 

There are three principal morphologies associated with epithelial cells. Squamous epithelium has cells which are wider than they are tall (flat and scale-like). Cuboidal epithelium has cells whose height and width are approximately the same (cube shaped). Columnar epithelium has cells taller than they are wide (column shaped). In addition, the morphology of the cells in transitional epithelium may vary from squamous to cuboidal, depending on the amount of tension on the epithelium.

 

Simple epithelium

 

Simple epithelium is one cell thick, that is, every cell is in direct contact with the underlying basement membrane. It is generally found where absorption and filtration occur. The thinness of the epithelial barrier facilitates these processes.

 

Simple epithelial tissues are generally classified by the shape of their cells. The four major classes of simple epithelium are: (1) simple squamous; (2) simple cuboidal; (3) simple columnar; (4) pseudostratified.

 

Simple squamous epithelium is found lining areas where passive diffusion of gases occur. e.g. walls of capillaries, linings of the pericardial, pleural,and peritoneal cavities, as well as the linings of the alveoli of the lungs.

 

Functions

 

The primary functions of epithelial tissues are: (1) to protect the tissues that lie beneath it from radiation, desiccation, toxins, invasion by pathogens, and physical trauma; (2) the regulation and exchange of chemicals between the underlying tissues and a body cavity; (3) the secretion of hormones into the blood vascular system, and/or the secretion of sweat, mucus, enzymes, and other products that are delivered by ducts glandular epithelium; (4) to provide sensation.

 

Secretory epithelia

 

As stated above, secretion is one major function of epithelial cells. Glands are formed from the invagination / infolding of epithelial cells and subsequent growth in the underlying connective tissue. There are two major classifications of glands: endocrine glands and exocrine glands. Endocrine glands secrete their product into the extracellular space where it is rapidly taken up by the blood vascular system. The exocrine glands secrete their products into a duct that then delivers the product to the lumen of an organ or onto the free surface of the epithelium.

 

Sensing the extracellular environment

 

"Some epithelial cells are ciliated, and they commonly exist as a sheet of polarised cells forming a tube or tubule with cilia projecting into the lumen." Primary cilia on epithelial cells provide chemosensation, thermosensation and mechanosensation of the extracellular environment by playing "a sensory role mediating specific signalling cues, including soluble factors in the external cell environment, a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow, and mediation of fluid flow if the cilia are motile."

 

Embryological development

 

In general, there are epithelial tissues deriving from all of the embryological germ layers:

from ectoderm (e.g., the epidermis);

from endoderm (e.g., the lining of the gastrointestinal tract);

from mesoderm (e.g., the inner linings of body cavities).

 

However, it is important to note that pathologists do not consider endothelium and mesothelium (both derived from mesoderm) to be true epithelium. This is because such tissues present very different pathology. For that reason, pathologists label cancers in endothelium and mesothelium sarcomas, whereas true epithelial cancers are called carcinomas. Also, the filaments that support these mesoderm-derived tissues are very distinct. Outside of the field of pathology, it is, in general, accepted that the epithelium arises from all three germ layers.

 

Growing in culture

 

When growing epithelium in culture, one can determine whether or not a particular cell is epithelial by examining its morphological characteristics. Epithelial cells tend to cluster together, and have a "characteristic tight pavementlike appearance". But this is not always the case, such as when the cells are derived from a tumor. In these cases, it is often necessary to use certain biochemical markers to make a positive identification. The intermediate filament proteins in the cytokeratin group are almost exclusively found in epithelial cells, and so are often used for this purpose.

 

Location

 

Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermost layer of our skin is composed of dead stratified squamous, keratinized epithelial cells.

 

Tissues that line the inside of the mouth, the esophagus and part of the rectum are composed of nonkeratinized stratified squamous epithelium. Other surfaces that separate body cavities from the outside environment are lined by simple squamous, columnar, or pseudostratified epithelial cells. Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive and urinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea is covered with fast-growing, easily-regenerated epithelial cells. Endothelium (the inner lining of blood vessels, the heart, and lymphatic vessels) is a specialized form of epithelium. Another type, mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.

Connective tissue: Connects different structures of the body & also helps to provide framework of the body. e.g. – Blood, Bones. Connective tissues are fibrous tissues. They are made up of cells separated by non-living material, which is called extracellular matrix. Connective tissue gives shape to organs and holds them in place. Both blood and bone are examples of connective tissue. As the name. It supports and binds other tissues. Unlike epithelial tissue, connective tissue typically has cells scattered throughout an extracellular matrix2.

All CT has three main components: cells, fibers, and extracellular matrix, all immersed in the body fluids.

 

Connective tissue can be broadly subdivided into connective tissue proper, special connective tissue, and series of other, less classifiable types of connective tissues. Connective tissue proper consists of loose connective tissue and dense connective tissue (which is further subdivided into dense regular and dense irregular connective tissues.) Special connective tissue consists of reticular connective tissue, adipose tissue, cartilage, bone, and blood. Other kinds of connective tissues include fibrous, elastic, and lymphoid connective tissues.

 

Fibroblasts are the cells responsible for the production of some CT.

 

Type-I collagen, is present in many forms of connective tissue, and makes up about 25% of the total protein content of the mammalian body.

Functions of connective tissue

Storage of energy

Protection of organs

Provision of structural framework for the body

Connection of body tissues

Connection of epithelial tissues to muscle tissues

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Characteristics of connective tissue and fiber types

 

Characteristics of CT:

Cells are spread through an extracellular fluid.

Ground substance - A clear, colorless, and viscous fluid containing glycosaminoglycans and proteoglycans to fix the bodywater and the collagen fibers in the intercellular spaces. Ground substance slows the spread of pathogens.

Fibers. Not all types of CT are fibrous. Examples include adipose tissue and blood. Adipose tissue gives "mechanical cushioning" to our body, among other functions. Although there is no dense collagen network in adipose tissue, groups of adipose cells are kept together by collagen fibers and collagen sheets in order to keep fat tissue under compression in place (for example, the sole of the foot). The matrix of blood is plasma.

Both the ground substance and proteins (fibers) create the matrix for CT.

 

Types of fibers:

·        Collagenous fibers        . Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of vertebrates. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc. The fibroblast is the most common cell which creates collagen.

In muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles. Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed.

 

 

Tropocollagen triple helix

History and background

 

The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s. Since that time, many prominent scholars, including Nobel laureates Crick, Pauling, Rich and Yonath, and others, including Brodsky, Berman, and Ramachandran, concentrated on the conformation of the collagen monomer. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model, which provided an essentially correct model of the molecule's quaternary structure although this model still required some refinement. The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal or quasi-hexagonal. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar. The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy. The microfibrillar structure of adult tendon, as described by Fraser, Miller, and Wess (amongst others), was modeled as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril. Various cross linking agents like dopaquinone, embelin, potassium embelate and 5-O-methyl embelin could be developed as potential cross-linking/stabilization agent of collagen preparation and its application as wound dressing sheet in clinical applications is enhanced.

 

Chemistry

 

Collagen is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2). The amino acid composition of collagen is atypical for proteins, particularly with respect to its high hydroxyproline content. The most common motifs in the amino acid sequence of collagen are glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.

 

Synthesis

 

First, a three dimensional stranded structure is assembled, with the amino acids lycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. A recent study shows that vitamin C must have an important role in its synthesis. Prolonged exposure of cultures of human connective-tissue cells to ascorbate induced an eight-fold increase in the synthesis of collagen with no increase in the rate of synthesis of other proteins (Murad et al., 1981). Since the production of procollagen must precede the production of collagen, vitamin C must have a role in this step. The conversion involves a reaction that substitutes a hydroxyl group, OH, for a hydrogen atom, H, in the proline residues at certain points in the polypeptide chains, converting those residues to hydroxyproline. This hydroxylation reaction organizes the chains in the conformation necessary for them to form a triple helix. The hydroxylation, next, of the residues of the amino acid lysine, transforming them to hydroxylysine, is then needed to permit the cross-linking of the triple helices into the fibers and networks of the tissues.

 

These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions. in this service, one molecule of vitamin C is destroyed for each H replaced by OH. The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems is the other form of collagen. It should be noted that all types of collagens are triple helixes, and the differences lie in the make-up of the alpha peptides created in step 2.

Transcription of mRNA: There are approximately 34 genes associated with collagen formation, each coding for a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).

Pre-pro-peptide Formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal recognition particle on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. Note that it is now known as pre-pro-collagen.

Alpha Peptide to Procollagen: Three modifications of the pre-pro-peptide occurs leading to the formation of the alpha peptide. Secondly, the triple helix known as procollagen is formed before being transported in a transport vesicle to the golgi apparatus. 1) The signal peptide on the N-terminal is dissolved, and the molecule is now known as propeptide (not procollagen). 2) Hydroxylation of lysines and prolines on propeptide by the enzymes prolyl hydroxylase and lysyl hydroxylase (to produce hydroxyproline and hydroxylysine) occurs to aid crosslinking of the alpha peptides. It is this enzymatic step that requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by 3 alpha peptides). 3) Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxy groups that were placed onto lysines, but not on prolines. From here the hydroxylated and glycosylated propeptide twists towards the left very tightly and then three propeptides will form a triple helix. It is important to remember that this molecule, now known as procollagen (not propeptide) is composed of a twisted portion (center) and two loose ends on either end. At this point the procollagen is packaged into a transfer vesicle destined for the golgi apparatus.

Golgi Apparatus Modification: In the golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step oligosaccharides (not monosaccharides like in step 3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.

Formation of Tropocollagen: Once outside the cell, membrane bound enzymes known as collagen peptidases, remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defect in this step produces one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is absent when synthesizing type III, a type of fibrilar collagen.

Formation of the Collagen Fibril: Lysyl oxidase and extracellular enzyme produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.

Action of lysyl oxidase

 

Amino acids

 

Collagen has an unusual amino acid composition and sequence:

Glycine is found at almost every third residue

Proline (Pro) makes up about 17% of collagen

Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.

Hydroxyproline (Hyp), derived from proline.

Hydroxylysine (Hyl), derived from lysine (Lys). Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated (mostly having disaccharides attached).

 

Cortisol stimulates degradation of (skin) collagen into amino acids.[28]

 

Collagen I formation

 

Most collagen forms in a similar manner, but the following process is typical for type I:

Inside the cell

1.     Two types of peptide chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.

2.     Polypeptide chains are released into the lumen of the RER.

3.     Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.

4.     Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (Vitamin C) as a cofactor.

5.     Glycosylation of specific hydroxylysine residues occurs.

6.     Triple ɣ helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.

7.     Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted by exocytosis.

Outside the cell

1.     Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.

2.     Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.

3.     Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.

 

Synthetic pathogenesis

 

Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C.

 

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis may attack healthy collagen fibers.

 

Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

 

Molecular structure

 

The tropocollagen or collagen molecule is a subunit of larger collagen aggregates such as fibrils. At approximately 300 nm long and 1.5 nm in diameter, it is made up of three polypeptide strands (called alpha peptides, see step 2), each possessing the conformation of a left-handed helix (its name is not to be confused with the commonly occurring alpha helix, a right-handed structure). These three left-handed helices are twisted together into a right-handed coiled coil, a triple helix or "super helix", a cooperative quaternary structure stabilized by numerous hydrogen bonds. With type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.

 

A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues. Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. About 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine, and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small methyl group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of their sequence. Chemically-reactive side groups are not needed in structural proteins, as they are in enzymes and transport proteins; however, collagen is not quite just a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its nonproline-rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.

 

Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish, whose body temperatures are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals. The lower proline and hydroxproline contents of cold-water fish and other poikilotherm animals leads to their collagen having a lower thermal stability than mammalian collagen. This lower thermal stability means that gelatin derived from fish collagen is not suitable for many food and industrial applications.

 

The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. In the fibrillar collagens, the molecules are staggered from each other by about 67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing only four molecules, called the "gap". The triple-helices are also arranged in a hexagonal or quasihexagonal array in cross-section, in both the gap and overlap regions.

 

There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils). Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players. Collagen's insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell-cell and cell-matrix communication, and how tissues are constructed in growth and repair, and changed in development and disease. For example using AFM –based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.

 

Collagen fibrils are semicrystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.

 

Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) Ca10(OH)2(PO4)6. Type I collagen gives bone its tensile strength.

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Types and associated disorders

 

Collagen occurs in many places throughout the body. Over 90% of the collagen in the body, however, is of type I.

 

So far, 28 types of collagen have been identified and described. The five most common types are:

·        Collagen I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)

·        Collagen II: cartilage (main component of cartilage)

·        Collagen III: reticulate (main component of reticular fibers), commonly found alongside type I.

·        Collagen IV: forms bases of cell basement membrane

·        Collagen V: cell surfaces, hair and placenta

·        Elastic fibers. Elastic fibers (or yellow fibers) are bundles of proteins (elastin) found in extracellular matrix of connective tissue and produced by fibroblasts and smooth muscle cells in arteries. These fibers can stretch up to 1.5 times their length, and snap back to their original length when relaxed. Elastic fibers include elastin, elaunin and oxytalan.

Elastic tissue is classified as "connective tissue proper".

The elastic fiber is formed from the elastic microfibril (consisting of numerous proteins such as microfibrillar-associated glycoproteins, fibrillin, fibullin, and the elastin receptor) and amorphous elastin.

The microfibril scaffolds and organizes the deposition of amorphous elastin. Amorphous elastin forms from monomers of soluble tropoelastin which is insolubilized and crosslinked into amorphous elastin by lysyl oxidase. Lysyl oxidase reacts with specific lysine residues and by oxidative deamination generates reactive aldehydes and allysine.

These reactive aldehydes and allysines can react with lysine and other allysine residues to crosslink and form desmosine, isodesmosine, and a number of other polyfunctional crosslinks that join surrounding elastin molecules to build an elastin matrix and elastic fiber. These unique crosslinks are responsible for elastin's elasticity.

Subcutaneous tissue from a young rabbit. Highly magnified. (Elastic fibers labeled at right. )

Histology

 

Elastic fibers stain well with aldehyde fuchsin, orcein, and Weigert's elastic stain in histological sections.

 

The permanganate-bisulfite-toluidine blue reaction is a highly selective and sensitive method for demonstrating elastic fibers under polarizing optics. The induced birefringence demonstrates the highly ordered molecular structure of the elastin molecules in the elastic fiber. This is not readily apparent under normal optics.

 

Defects and disease

 

There is evidence to believe that certain defects of any components of the elastic matrix may impair and alter the structural appearance of elastic and collagen fibers.

 

Cutis laxa and Williams syndrome have elastic matrix defects that have been directly associated with alterations in the elastin gene.

 

Alpha-1 antitrypsin deficiency is a genetic disorder where elastin is excessively degraded by elastase, a degrading protein released by neutrophils during the inflammatory response. This leads most often to emphysema and liver disease in affected individuals.

 

Buschke-Ollendorff syndrome, Menkes disease, pseudoxanthoma elasticum, and Marfan's syndrome have been associated with defects in copper metabolism and lysyl oxidase or defects in the microfibril (defects in fibrillin, or fibullin for example).

 

Hurler disease, a lysosomal storage disease, is associated with an altered elastic matrix.

 

Hypertension and some congenital heart defects are associated with alterations in the great arteries, arteries, and arterioles with alterations in the elastic matrix.

·        Reticular fibers. Reticular fibers, reticular fibres or reticulin is a type of fiber in connective tissue composed of type III collagen secreted by reticular cells. Reticular fibers crosslink to form a fine meshwork (reticulin). This network acts as a supporting mesh in soft tissues such as liver, bone marrow, and the tissues and organs of the lymphatic system.

A liver biopsy stained with a reticulin stain demonstrating a normal hepatic plate thickness and mild steatosis.

History

 

The term reticulin was coined in 1892 by M. Siegfried.

 

Today, the term reticulin or reticular fiber is restricted to referring to fibers composed of type III collagen. However, during the pre-molecular era, there was confusion in the use of the term 'reticulin', which was used to describe two structures:

the argyrophilic (silver staining) fibrous structures present in basement membranes

histologically similar fibers present in developing connective tissue.

 

The history of the reticulin silver stain is reviewed by Puchtler et al. (1978). The abstract of this paper says:

 

Maresch (1905) introduced Bielschowsky's silver impregnation technic for neurofibrils as a stain for reticulum fibers, but emphasized the nonspecificity of such procedures. This lack of specificity has been confirmed repeatedly. Yet, since the 1920s the definition of "reticulin" and studies of its distribution were based solely on silver impregnation technics. The chemical mechanism and specificity of this group of stains is obscure. Application of Gömöri's and Wilder's methods to human tissues showed variations of staining patterns with the fixatives and technics employed. Besides reticulum fibers, various other tissue structures, e.g. I bands of striated muscle, fibers in nervous tissues, and model substances, e.g. polysaccharides, egg white, gliadin, were also stained. Deposition of silver compounds on reticulum fibers was limited to an easily removable substance; the remaining collagen component did not bind silver. These histochemical studies indicate that silver impregnation technics for reticulum fibers have no chemical significance and cannot be considered as histochemical technics for "reticulin" or type III collagen.

 

Structure

 

Reticular fiber is composed of one or more types of very thin and delicately woven strands of type III collagen. These strands build a highly ordered cellular network and provide a supporting network. Many of these types of collagen have been combined with carbohydrate. Thus, they react with silver stains and with periodic acid-Schiff reagent but are not demonstrated with ordinary histological stains such as those using hematoxylin. The 1953 Science article mentioned above concluded that the reticular and regular collagenous materials contains the same four sugars—galactose, glucose, mannose, and fucose—but in a much greater concentration in the reticular than in the collagenous material.

 

In a 1993 paper, the reticular fibers of the capillary sheath and splenic cord were studied and compared in the pig spleen by transmission electron microscopy. This paper attempted to reveal their components and the presence of sialic acid in the amorphous ground substance. Collagen fibrils, elastic fibers, microfibrils, nerve fibers, and smooth muscle cells were observed in the reticular fibers of the splenic cord. On the other hand, only microfibrils were recognized in the reticular fibers of the capillary sheath. The binding of LFA lectin to the splenic cord was stronger than the capillary sheath. These findings suggested that the reticular fibers of the splenic cord include multiple functional elements and might perform an important role during contraction or dilation of the spleen. On the other hand, the reticular fiber of the capillary sheath resembled the basement membrane of the capillary in its components.

Muscular tissue: Muscular tissues make up the major part of the soft tissues of the body & by means of its contraction power helps in locomotion. e.g. – Skeletal muscle, cardiac muscle. Muscle cells form the active contractile tissue of the body known as muscle tissue or muscular tissue. Muscle tissue functions to produce force and cause motion, either locomotion or movement within internal organs. Muscle tissue is separated into three distinct categories: visceral or smooth muscle, which is found in the inner linings of organs; skeletal muscle, in which is found attached to bone providing for gross movement; and cardiac muscle which is found in the heart, allowing it to contract and pump blood throughout an organism.

Nervous tissue: Nervous tissue is highly specialized tissue which controls & co-ordinates the body functions by forming nervous system. e.g – Neuralgia, White matter, Grey matter. Cells comprising the central nervous system and peripheral nervous system are classified as neural tissue. In the central nervous system, neural tissue forms the brain and spinal cord and, in the peripheral nervous system forms the cranial nerves and spinal nerves, inclusive of the motor neurons. Nervous tissue functions to transmit messages in form of impulse.

Tissue in the human body:

 

1.     Epithelial: Is made of cells arranged in a continuous sheet with one or more layers, has apical & basal surfaces.

o        A basement membrane is the attachment between the basal surface of the cell & the underlying connective tissue.

o        Two types of epithelial tissues: (1) Covering & lining epithelia and (2) Glandular Epithelium.

o        The number of cell layers & the shape of the cells in the top layer can classify epithelium.

§         Simple Epithelium - one cell layer

§         Stratified epithelium - two or more cell layers

§         Pseudostratified Columnar Epithelium - When cells of an epithelial tissue are all anchored to the basement Membrane but not all cells reach the apical surface.

§         Glandular Epithelium – (1) Endocrine: Release hormones directly into the blood stream and (2) Exocrine - Secrete into ducts.

 

2.     Connective: contains many different cell types including: fibroblasts, macrophages, mast cells, and adipocytes. Connective Tissue Matrix is made of two materials: ground substance - proteins and polysaccharides, fiber – reticular, collagen and elastic.

Classification of Connective Tissue:

o        oose Connective - fibers & many cell types in gelatinous matrix, found in skin, & surrounding blood vessels, nerves, and organs.

o        Dense Connective - Bundles of parallel collagen fibers& fibroblasts, found in tendons& ligaments.

o        Cartilage - Cartilage is made of collagen & elastin fibers embedded in a matrix glycoprotein & cells called chondrocytes, which was found in small spaces.

o        Cartilage has three subtypes:

§         Hyaline cartilage – Weakest, most abundant type, Found at end of long bones, & structures like the ear and nose,

§         Elastic cartilage- maintains shape, branching elastic fibers distinguish it from hyaline and

§         Fibrous Cartilage - Strongest type, has dense collagen & little matrix, found in pelvis, skull & vertebral discs.

3.     Muscle: is divided into 3 categories, skeletal, cardiac and smooth.

o        Skeletal Muscle – voluntary, striated, striations perpendicular to the muscle fibers and it is mainly found attached to bones.

o        Cardiac Muscle – involuntary, striated, branched and has intercalated discs

o        Smooth Muscle – involuntary, nonstriated, spindle shaped and is found in blood vessels & the GI tract.

4.     Nervous: Consists of only two cell types in the central nervous system (CNS) & peripheral nervous system (PNS):

o        Neurons - Cells that convert stimuli into electrical impulses to the brain, and Neuroglia – supportive cells.

o        Neurons – are made up of cell body, axon and dendrites. There are 3 types of neurons:

§         Motor Neuron –  carry impulses from CNS to muscles and glands,

§         Interneuron - interpret input from sensory neurons and end responses to motor neurons

§         Sensory Neuron – receive information from environment and transmit to CNS.

o        Neuroglia – is made up of astrocytes, oligodendrocytes, ependymal cells and microglia in the CNS, and schwann cells and satellite cells in the PNS.

Development: All tissues of the body develop from the three primary germ cell layers that form the embryo:

  • Mesoderm – develops into epithelial tissue, connective tissue and muscle tissue.
  • Ectoderm - develops into nervous tissue and epithelial tissue.
  • Endoderm – develops into epithelial tissue.

Cell Junctions:

  • Tight Junctions - Form a seal between cells, define apical and basal sides of an epithelial cell
  • Gap Junctions - An open junction between two cells, which allows ions, & small molecules to pass freely between the cells.
  • Adherens Junctions - Link actin cytoskeletal elements in two cells.
  • Desmosomes - Link keratin filaments in adjoining cells and resist shearing forces.
  • Hemidesmosomes - Anchor keratin fibers in epithelial cells to the basement membrane through integrin anchors.

 

 

 


What Is An Adjective?

An adjective modifies a noun or a pronoun by describing, identifying, or quantifying words. An adjective usually precedes the noun or the pronoun which it modifies.

In the following examples, the highlighted words are adjectives:

The truck-shaped balloon floated over the treetops.

Mrs. Morrison papered her kitchen walls with hideous wall paper.

The small boat foundered on the wine dark sea.

The coal mines are dark and dank.

Many stores have already begun to play irritating Christmas music.

A battered music box sat on the mahogany sideboard.

The back room was filled with large, yellow rain boots.

An adjective can be modified by an adverb, or by a phrase or clause functioning as an adverb. In the sentence

My husband knits intricately patterned mittens.

for example, the adverb ``intricately'' modifies the adjective ``patterned.''

Some nouns, many pronouns, and many participle phrases can also act as adjectives. In the sentence

Eleanor listened to the muffled sounds of the radio hidden under her pillow.

for example, both highlighted adjectives are past participles.

Grammarians also consider articles (``the,'' ``a,'' ``an'') to be adjectives.

Possessive Adjectives

A possessive adjective (``my,'' ``your,'' ``his,'' ``her,'' ``its,'' ``our,'' ``their'') is similar or identical to a possessive pronoun; however, it is used as an adjective and modifies a noun or a noun phrase, as in the following sentences:

I can't complete my assignment because I don't have the textbook.

In this sentence, the possessive adjective ``my'' modifies ``assignment'' and the noun phrase ``my assignment'' functions as an object. Note that the possessive pronoun form ``mine'' is not used to modify a noun or noun phrase.

What is your phone number.

Here the possessive adjective ``your'' is used to modify the noun phrase ``phone number''; the entire noun phrase ``your phone number'' is a subject complement. Note that the possessive pronoun form ``yours'' is not used to modify a noun or a noun phrase.

The bakery sold his favourite type of bread.

In this example, the possessive adjective ``his'' modifies the noun phrase ``favourite type of bread'' and the entire noun phrase ``his favourite type of bread'' is the direct object of the verb ``sold.''

After many years, she returned to her homeland.

Here the possessive adjective ``her'' modifies the noun ``homeland'' and the noun phrase ``her homeland'' is the object of the preposition ``to.'' Note also that the form ``hers'' is not used to modify nouns or noun phrases.

We have lost our way in this wood.

In this sentence, the possessive adjective ``our'' modifies ``way'' and the noun phrase ``our way'' is the direct object of the compound verb ``have lost''. Note that the possessive pronoun form ``ours'' is not used to modify nouns or noun phrases.

In many fairy tales, children are neglected by their parents.

Here the possessive adjective ``their'' modifies ``parents'' and the noun phrase ``their parents'' is the object of the preposition ``by.'' Note that the possessive pronoun form ``theirs'' is not used to modify nouns or noun phrases.

The cat chased its ball down the stairs and into the backyard.

In this sentence, the possessive adjective ``its'' modifies ``ball'' and the noun phrase ``its ball'' is the object of the verb ``chased.'' Note that ``its'' is the possessive adjective and ``it's'' is a contraction for ``it is.''

Demonstrative Adjectives

The demonstrative adjectives ``this,'' ``these,'' ``that,'' ``those,'' and ``what'' are identical to the demonstrative pronouns, but are used as adjectives to modify nouns or noun phrases, as in the following sentences:

When the librarian tripped over that cord, she dropped a pile of books.

In this sentence, the demonstrative adjective ``that'' modifies the noun ``cord'' and the noun phrase ``that cord'' is the object of the preposition ``over.''

This apartment needs to be fumigated.

Here ``this'' modifies ``apartment'' and the noun phrase ``this apartment'' is the subject of the sentence.

Even though my friend preferred those plates, I bought these.

In the subordinate clause, ``those'' modifies ``plates'' and the noun phrase ``those plates'' is the object of the verb ``preferred.'' In the independent clause, ``these'' is the direct object of the verb ``bought.''

Note that the relationship between a demonstrative adjective and a demonstrative pronoun is similar to the relationship between a possessive adjective and a possessive pronoun, or to that between a interrogative adjective and an interrogative pronoun.

Interrogative Adjectives

An interrogative adjective (``which'' or ``what'') is like an interrogative pronoun, except that it modifies a noun or noun phrase rather than standing on its own:

Which plants should be watered twice a week?

Like other adjectives, ``which'' can be used to modify a noun or a noun phrase. In this example, ``which'' modifies ``plants'' and the noun phrase ``which paints'' is the subject of the compound verb ``should be watered'':

What book are you reading?

In this sentence, ``what'' modifies ``book'' and the noun phrase ``what book'' is the direct object of the compound verb ``are reading.''

Indefinite Adjectives

An indefinite adjective is similar to an indefinite pronoun, except that it modifies a noun, pronoun, or noun phrasé́́́́, as in the following sentences:

Many people believe that corporations are under-taxed.

The indefinite adjective ``many'' modifies the noun ``people'' and the noun phrase ``many people'' is the subject of the sentence.

I will send you any mail that arrives after you have moved to Sudbury.

The indefinite adjective ``any'' modifies the noun ``mail'' and the noun phrase ``any mail'' is the direct object of the compound verb ``will send.''

They found a few goldfish floating belly up in the swan pound.

In this example the indefinite adjective modifies the noun ``goldfish'' and the noun phrase is the direct object of the verb ``found'':

The title of Kelly's favourite game is ``All dogs go to heaven.''

Here the indefinite pronoun ``all'' modifies ``dogs'' and the full title is a subject complement.

́́́́ THE COMPARISON OF ADJECTIVES

There are three degrees of comparison:
POSITIVE degree, COMPARATIVE degree, SUPERLATIVE degree:

POSITIVE

COMPARATIVE

SUPERLATIVE

cool

cooler

coolest

intelligent

more intelligent

most intelligent


01. COMPARATIVE OF EQUALITY

AS .... AS (for positive comparisons),
(NOT) SO .... AS (for negative comparisons).

Her pronunciation is AS good AS yours.
His pronunciation is NOT SO good AS yours.

Note: We may say NOT AS .... AS, especially after a contracted form: Her pronunciation isn't AS good AS yours.


02. COMPARATIVE OF INFERIORITY

LESS ..... THAN + the adjective.

It is LESS cold today THAN it was yesterday.
Kelly is LESS old THAN Sandra.


03. SUPERLATIVE OF INFERIORITY

THE LEAST ....... OF (or IN) + the adjective.

Sunday was THE LEAST cold day of the week.
Christina is THE LEAST old girl in that class.


04. COMPARATIVE and SUPERLATIVE OF SUPERIORITY

a) Monosyllabic adjectives form their COMPARATIVE and SUPERLATIVE by adding - ER and - EST to the POSITIVE degree.

tall

tallER THAN

THE tallEST

warm

warmER THAN

THE warmEST

Exceptions:

just

MORE just THAN

THE MOST just

right

MORE right THAN

THE MOST right

real

MORE real THAN

THE MOST real

wrong

MORE wrong THAN

THE MOST wrong

b) Adjectives with more than two syllables form their COMPARATIVE and SUPERLATIVE by putting MORE and THE MOST in front of the adjective.

difficult

MORE difficult THAN

THE MOST difficult

important

MORE important THAN

THE MOST important


c) Disyllabic (two syllables) adjectives form their COMPARATIVE and SUPERLATIVE in two different ways:

1. Adjectives ending in ED, ING, RE, FUL, OUS and those with the stress on the first syllable usually take MORE and THE MOST:

charming

MORE charming THAN

THE MOST charming

famous

MORE famous THAN

THE MOST famous

hopeful

MORE hopeful THAN

THE MOST hopeful

learned

MORE learned THAN

THE MOST learned

obscure

MORE obscure THAN

THE MOST obscure


2. Adjectives ending in ER, Y, LE, OW and those with the stress on the second syllable add ER and EST to the POSITIVE degree.

clever

cleverER THAN

THE cleverEST

narrow

narrowER THAN

THE narrowEST

pretty

prettiER THAN

THE prettiEST

polite

politER THAN

THE politEST

simple

simplER THAN

THE simplEST

Note: Adjectives ending in SOME and the words cheerful, common, cruel, pleasant, quiet, civil may be compared by adding ER and EST or by MORE and MOST.

pleasant

pleasantER THAN

THE pleasantEST

or

pleasant

MORE pleasant THAN

THE MOST pleasant


05. ORTHOGRAPHIC NOTES
a) Add R and ST to adjectives ending in E.

large

largeR THAN

THE largeST

ripe

ripeR THAN

THE ripeST

b) VOWEL SANDWICH (VOWEL + CONSONANT + VOWEL) (THE LAST VOWEL IS DOUBLED)

big

bigGER THAN

THE bigGEST

fat

fatTER THAN

THE fatTEST

NO SANDWICH (JUST THE SUFFIX)

small

smallER THAN

THE smallEST

sweet

sweetER THAN

THE sweetEST

c) Adjectives ending in - y preceded by a consonant, change Y into I before ER and EST.

happY

happIER THAN

THE happIEST

Exceptions:

shY

shYER THAN

THE shYEST

gaY

gaYER THAN

THE gaYEST

greY

greYER THAN

THE greYEST


6. IRREGULAR COMPARISONS

good

better than

the best

bad

worse than

the worst

little

less than

the least

much

more than

the most

many

more than

the most

far

farther than

the farthest

far

further than

the furthest

old

older than

the oldest

old

elder than

the eldest

NOTES:
1. FARTHER and FARTHEST generally refer to distance; FURTHER and FURTHEST also refer to distance but they may have the meaning of "additional".
I live farther from here than you do.
Give me further details.

2. OLDER and OLDEST refer to persons or things; ELDER and ELDEST can only be used for members of the same family:
My elder sister is afraid of mice.
My older friend is afraid of wasps.

but ELDER can not be placed before THAN so OLDER is used:
My sister is two years older than I am.


7. CONSTRUCTIONS WITH COMPARATIVES

a) Gradual increase:
Those exercises are getting EASIER AND EASIER. OR
Those exercises are getting MORE AND MORE EASY.

The weather is getting NICER AND NICER. OR
The weather is getting MORE AND MORE NICE.

The rent of our flat is getting MORE AND MORE EXPENSIVE.


B) Parallel increase: (THE + comparative ...... THE + comparative).
THE MORE
I see you THE MORE I want you.
THE HOTTER, THE BETTER.
THE MORE
he studies, THE BETTER he becomes.


COMPARISON OF ADVERBS

1. COMPARATIVE and SUPERLATIVE of SUPERIORITY.

a) Monosyllabic adverbs from their comparative and superlative of superiority in the same way as monosyllabic adjectives.

high

highER THAN

THE highEST

soon

soonER THAN

THE soonEST

fast

fastER THAN

THE fastEST

b) Adverbs of more than one syllable take MORE and MOST.

quickly

MORE quickly THAN

THE MOST quickly

slowly

MORE slowly THAN

THE MOST slowly

seldom

MORE seldom THAN

THE MOST seldom

Exception:

early

earliER THAN

THE earliEST


2. IRREGULAR COMPARISONS

well

better than

the best

badly

worse than

the worst

little

less than

the least

much

more than

the most

late

later than

the last

 

Tissue

Biological tissue is a collection of interconnected cells that perform a similar function within an organism.

The study of tissue is known as histology, or, in connection with disease, histopathology.

The classical tools for studying the tissues are the wax block, the tissue stain, and the optical microscope, though developments in electron microscopy, immunofluorescence, and frozen sections have all added to the sum of knowledge in the last couple of decades.With these tools, the classical appearances of the tissues can be examined in health and disease, enabling considerable refinement of clinical diagnosis and prognosis. There are four basic types of tissue in the body of all animals, including the human body and lower multicellular organisms such as insects. These compose all the organs, structures and other contents.

·                    Epithelium - Tissues composed of layers of cells that cover organ surfaces such as surface of the skin and inner lining of digestive tract: the tissues that serve for protection, secretion, and absorption.

·                    Connective tissue - As the name suggests, connective tissue holds everything together. Some people consider blood a connective tissue. It should be noted that blood is not 'considered' connective tissue, it is connective tissue. (i.e. cells of connective tissue (blood) separated by an inorganic material (plasma). Plasma is the extracellular matrix that includes everything but the red/white blood cells. These tissues contain extensive extracellular matrix.

·                    Muscle tissue - Muscle cells contain contractile filaments that move past each other and change the size of the cell. Muscle tissue also is separated into three distinct categories: visceral or smooth muscle, which is found in the inner linings of organs; skeletal muscle, which is found attached to bone in order for mobility to take place; and cardiac muscle which is found in the heart.

·                    Nervous tissue - Cells forming the brain, spinal cord and peripheral nervous system.

 

CARDINAL NUMERALS

CARDINAL NUMERALS


Cardinal numerals express integer (whole) abstract numbers or the number/amount of the determined nouns in literal form.


CARDINAL NUMERALS

 

Number

Literal form

 

0

zero; naught; null

1

one

2

two

3

three

10

ten

11

eleven

12

twelve

13

thirteen

24

twenty-four

67

sixty-seven

589

five hundred eighty-nine

310 533

three hundred ten thousand five hundred thirty-three

1 000 000

one/a million

1 000 000 000

one/a billion

1 000 000 000 000

one/a trillion

 

 

Cardinal numerals may also be:
1. adjective
2. noun
3. numeral "one" can also be a pronoun

ORDINAL NUMERALS


Ordinal numeral is used to express the order in a series.


ORDINAL NUMERALS

 

Position

Literal expression

 

 

1st

first

2nd

second

3rd

third

4th

fourth

5th

fifth

11th

eleventh

12th

twelfth

13th

thirteenth

20th

twentieth

21st

twenty-first

32nd

thirty-second

73rd

seventy-third

89th

eighty-ninth

137th

one hundred thirty-seventh

 

Ordinal numerals may also work as:
1. adjectives
2. nouns
3. adverbs

FRACTIONAL NUMERALS


Fractional numeral is used to express parts of a whole. Commonly, it takes two forms:

1. Common Fraction:

Form: Wholes + Numerator/Denominator

1 2/3     = one (whole) and/plus two thirds

Note the "s" added to the denominator "thirds".

2. Decimal Numbers:

12.15     = twelve fifteen, or twelve point fifteen

COLLECTIVE NUMERALS


Collective numerals are old forms of expression; they are used to express in singular form values having plural meaning.
Examples:
a couple; a dozen; etc.
They are
a very happy couple.

Collective numerals are commonly employed as:
1. adjectives
2. nouns

DISTRIBUTIVE NUMERALS


Distributive numerals are used to group units/objects expressed by nouns:
1. one at a time; three at a time;
2. one by one; ten by ten;
3. by twos; by fives; by tens; etc.


Examples:
She runs down
five steps at a time.

MULTIPLICATIVE NUMERALS


Multiplicative numeral is used to express the "growth rate" of a quantity, or the progression of an action. Some forms are: single; double; twofold; triple; etc.

Few Latin forms are also used, especially when multiplicative numeral is used as adjective: quadruple; quintuple; etc.

Multiplicative numerals are used as (details are presented in LSEG):
1. adjectives
2. adverbs

3. nouns (seldom)

ADVERBIAL NUMERALS


Adverbial numerals group all categories of numerals transformed into adverbs, plus few specific forms. They are used:
1. To express the frequency or the period of an action: frequently; seldom; from time to time; etc.
2. To show the place in a series: middle; towards the middle; end; the end; towards the end; etc.
3. To express the manner in which the action is performed: once; twice; thrice; ten times; once more; once again; twice as fast; etc
4. To structure concepts/actions logically: firstly; secondly; thirdly; fourthly; etc.

INDEFINITE NUMERALS


Indefinite numerals are used to express vague, imprecise numbers/values/amounts. There are very many forms of indefinite numerals; for example: several; many; a few; some; a number of; etc.

TECHNICAL NUMERALS


Technical numeral is a new addition due to technological development.
The most common forms it takes are:


SCIENTIFIC NUMERALS

 

 

 

Number

Notation (symbol)

Name

 

 

 

10-12 = 0.000 000 000 001

p

pico

10-9 = 0.000 000 001

n

mano

10-6 = 0.000 001

μ or u

micro

10-3 = 0.001

m

milli

103 = 1000

K

kilo

106 = 1 000 000

M

mega

109 = 1 000 000 000

G

giga

1012 = 1 000 000 000 000

T

terra

 

 

 

 

 

Cellular differentiation

 

 

In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of tissues and cell types. Differentiation is a common process in adults as well: adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.

A cell that is able to differentiate into all cell types of the adult organism is known as pluripotent. Such cells are called embryonic stem cells in animals and meristematic cells in higher plants. A cell that is able to differentiate into all cell types, including the placental tissue, is known as totipotent. In mammals, only the zygote and subsequent blastomeric are totipotent, while in plants many differentiated cells can become totipotent with simple laboratory techniques. In cytopathology, the level of cellular differentiation is used as a measure of cancer progression. "Grade" is a marker of how differentiated a cell in a tumor is.

Mammalian cell types

 

Three basic categories of cells make up the mammalian body: germ cells, somatic cells, and stem cells. Each of the approximately 100 trillion (1014) cells in an adult human has its own copy or copies of the genome except certain cell types, such as red blood cells, that lack nuclei in their fully differentiated state. Most cells are diploid; they have two copies of each chromosome. Such cells, called somatic cells, make up most of the human body, such as skin and muscle cells. Cells differentiate to specialize for different functions.

Germ line cells are any line of cells that give rise to gametes—eggs and sperm—and thus are continuous through the generations. Stem cells, on the other hand, have the ability to divide for indefinite periods and to give rise to specialized cells. They are best described in the context of normal human development.

Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming a hollow sphere of cells, called a blastocyst. The blastocyst has an outer layer of cells, and inside this hollow sphere, there is a cluster of cells called the inner cell mass. The cells of the inner cell mass go on to form virtually all of the tissues of the human body. Although the cells of the inner cell mass can form virtually every type of cell found in the human body, they cannot form an organism. These cells are referred to as pluripotent.

Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include:

·                    Hematopoietic stem cells (adult stem cells) from the bone marrow that give rise to red blood cells, white blood cells, and platelets

·                    Mesenchyme stem cells (adult stem cells) from the bone marrow that give rise to stromal cells, fat cells, and types of bone cells

·                    Epithelial stem cells (progenitor cells) that give rise to the various types of skin cells

·                    Muscle satellite cells (progenitor cells) that contribute to differentiated muscle tissue.

A pathway that is guided by the cell adhesion molecules consisting of four amino acids, arginine, glycine, asparagine, and serine, is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm, mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming the skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues.

Dedifferentiation

220px-Dedifferentiated_liposarcoma_-_intermed_mag

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Micrograph of a lip sarcoma with some dedifferentiation, that is not identifiable as a liposarcoma, (left edge of image) and a differentiated component (with lip oblasts and increased vascularity (right of image)). Fully differentiated (morphologically benign)adipose tissue (center of the image) has few blood vessels. H&E stain.

Dedifferentiation is a cellular process often seen in more basal life forms such as worms and amphibians in which a partially or terminally differentiated cell reverts to an earlier developmental stage, usually as part of a regenerative process. Dedifferentiation also occurs in plants. Cells in cell culture can lose properties they originally had, such as protein expression, or change shape. This process is also termed dedifferentiation.

Some believe dedifferentiation is an aberration of the normal development cycle that results in cancer, whereas others believe it to be a natural part of the immune response lost by humans at some point as a result of evolution.

A small molecule dubbed riverine, a purine analog, has been discovered that has proven to induce dedifferentiation in my tubes. These dedifferentiated cells were then able to redifferentiate into osteoblasts and adipocytes.

lossy-page1-600px-Dedifferentiation_Methods_%282010%29_-_Bischoff%2C_Steven_R

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Dedifferentiation to totipotency or pluripotency: an overview of methods.'Various methods exist to revert adult somatic cells to pluripotency or totipotency. In the case of totipotency, reprogramming is mediated through a mature metaphase II oocyte as in somatic cell nuclear transfer (Wilmut et al., 1997). Recent work has demonstrated the feasibility of enucleated zygotes or early blastomeres chemically arrested during mitosis, such that nuclear envelope break down occurs, to support reprogramming to totipotency in a process called chromosome transfer (Egli and Eggan, 2010). Direct reprogramming methods support reversion to pluripotency; though, vehicles and biotypes vary considerably in efficiencies (Takahashi and Yamanaka, 2006). Viral-mediated transduction robustly supports dedifferentiation to pluripotency through retroviral or DNA-viral routes but carries the onus of insertional inactivation. Additionally, epigenetic reprogramming by enforced expression of OSKM through DNA routes exists such as plasmid DNA, minicircles, transposons, episomes and DNA mulicistronic construct targeting by homologous recombination has also been demonstrated; however, these methods suffer from the burden to potentially alter the recipient genome by gene insertion (Ho et al., 2010). While protein-mediated transduction supports reprogramming adult cells to pluripotency, the method is cumbersome and requires recombinant protein expression and purification expertise, and reprograms albeit at very low frequencies (Kim et al., 2009). A major obstacle of using RNA for reprogramming is its lability and that single-stranded RNA biotypes trigger innate antiviral defense pathways such as interferon and NF-κB-dependent pathways. In vitro transcribed RNA, containing stabilizing modifications such as 5-methylguanosine capping or substituted ribonucleobases, e.g. pseudouracil, is 35-fold more efficient than viral transduction and has the additional benefit of not altering the somatic genome (Warren et al., 2010).

Mechanisms

400px-Cell_Differentiation

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Mechanisms of cellular differentiation

Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species. Each cell type is defined by its particular pattern of regulated gene expression. Cell differentiation is thus a transition of a cell from one cell type to another and it involves a switch from one pattern of gene expression to another. Cellular differentiation during development can be understood as the result of a gene regulatory network. A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive input and create output elsewhere in the network. The systems biology approach to developmental biology emphasizes the importance of investigating how developmental mechanisms interact to produce predictable patterns (morphogenesis). (However, an alternative view has been proposed recently. Based on stochastic gene expression, cellular differentiation is the result of a Darwinian selective process occurring among cells. In this frame, protein and gene networks are the result of cellular processes and not their cause. See: Cellular)

A few evolutionarily conserved types of molecular processes are often involved in the cellular mechanisms that control these switches. The major types of molecular processes that control cellular differentiation involve cell signaling. Many of the signal molecules that convey information from cell to cell during the control of cellular differentiation are called growth factors. Although the details of specific signal transduction pathways vary, these pathways often share the following general steps. A ligand produced by one cell binds to a receptor in the extracellular region of another cell, inducing a conformational change in the receptor. The shape of the cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic activity. The receptor then catalyzes reactions that phosphorylate other proteins, activating them. A cascade of phosphorylation reactions eventually activates a dormant transcription factor or cytoskeletal protein, thus contributing to the differentiation process in the target cell. Cells and tissues can vary in competence, their ability to respond to external signals.

Signal Induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate. Yamamoto and Jeffery investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction. Through reciprocal transplants, Yamamoto and Jeffery found that the lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot.

Other important mechanisms fall under the category of asymmetric cell divisions, divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling. In the former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila. RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of the genus Volvos, a model system for studying how unicellular organisms can evolve into multicellular organisms. In Volvox carteri, the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell.

Epigenetic control of cellular differentiation

Since each cell, regardless of cell type, possesses the same genome, determination of cell type must occur at the level of gene expression. While the regulation of gene expression can occur through cist- and trans-regulatory elements including a gene’s promoter and enhancers, the problem arises to how this expression pattern is maintained over numerous generations of cell division. As it turns out, epigenetic processes play a crucial role in regulating the decision to adopt a stem, progenitor, or mature cell fate. This section will focus primarily on mammalian stem cells.

Importance of epigenetic control

The first question that can be asked is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, et al.  on aberrant epigenomic programming in human induced. As induced pluripotent stem cells (iPSCs) are thought to mimic embryonic stem cells in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction, the authors conducted whole-genome profiling of DNA methylation patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines.

Female adipose cells, lung fibroblasts, and foreskin fibroblasts were reprogrammed into induced pluripotent state with the OCT4,SOX2, KLF4, and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, et al. observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of CG dinucleotide in ESCs and iPSCs were methylated, the same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of cytosine methylation in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities, DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs.

However, upon examining methylation patterns more closely, the authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both the progenitor and embryonic cell lines. In vitro-induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively.

Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in cell fate determination, as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of transcription. Second, the mechanisms of de-differentiation (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation.

Mechanisms of epigenetic regulation

Three transcription factors, OCT4, SOX2, and NANOG – the first two of which are used in iPSC reprogramming – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency. It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit the transcription of target genes.

In the realm of gene silencing, Polycomb repressive complex 2, one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3). By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression. PcG knockout ES cells do not differentiate efficiently into the three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation  Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes.

Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but are unable to maintain the differentiated phenotype. Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression. TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 (H3K4me3) and promote gene activation through histone acetylation. PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what is termed a “bivalent domain” and rendering these genes sensitive to rapid induction or repression.

Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase-mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility. The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes. Upon differentiation, a small number of genes, including OCT4 and NANOG, are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation.

Role of signaling in epigenetic control

A final question to ask concerns the role of cell signaling in influencing the epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Interestingly, little direct data is available concerning the specific signals that influence the epigenome, and the majority of current knowledge consist of speculations on plausible candidate regulators of epigenetic remodeling. We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change.

The first major candidate is Wnt signaling pathway. The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells. On the other hand, disruption of ß-catenin, a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors.

Growth factors comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include bone morphogenetic proteins,transforming growth factors (TGFs), and fibroblast growth factors (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to Smad proteins. Depletion of growth factors promotes the differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription.

Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency. Retinoic acid can induce differentiation of human and mouse ESCs, and Notch signaling is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog, in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells.

The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them.

Expression of Shh (Sonic hedgehog) upregulates the production of Bmi1, a component of the PcG complex that recognizes H3K27me3. This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway. In culture, Bmi1 mediates the Hedgehog pathway’s ability to promote human mammary stem cell self-renewal. In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1 was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior. A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice.

In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate the likely existence of further such mechanisms.

Tissue stress

 

Tissue stress (tissue adaptive syndrome) is an unspecific adaptive reaction universal for all tissues of adult organism which forms in tissue as a response to various external influences. The latter are tissue cells’ damage, overload of their specialized functions or regulatory influences.

Tissue stress mechanism

According to tissue adaptive syndrome (TAS) concept, this adaptive mechanism (see adaptation) comes into effect in damaged tissue (see Tissue (biology)) as a result of concurrence of two events. The first one is accumulation of TAS effectors in tissue (comutons, chalones, and contactines), which possess a unique feature of tissue specificity in their action on homologous tissue cells without species specificity. The second one is increase in sensitivity of damaged cells to these regulators, as it was demonstrated on the example of comuton. These effectors cause tissuespecific self-damage of homologous cells via disturbance of their ion homeostasis and energy-production processes. As a result, unspecific reaction to damage (CURD) is activated in the cells. This universal physiological reaction plays a role of TAS executive mechanism. Thus, the adaptive function of tissue stress is brought into action using such CURD properties as increase of cell unspecific resistance, as well as influence on the rate of cell metabolic processes. It is obvious that in the case of TAS these changes have to be tissuespecific, since they are initiated by way of cell self-damage under tissuespecific influence of TAS effectors.

As is well known the CURD consists of two phases. In the process of a slight damage of the cell the phase of metabolism stimulation is forming in it. When the cell is slightly damaged, it begins to form the phase of metabolism stimulation. Strong damaging influences initiate the CURD phase of metabolism inhibition in the cell.

According to the TAS concept, the protective effect of the tissue stress is realized in the case of forming of CURD metabolism stimulation phase by TAS effectors as a result of acceleration of reparative processes in the damaged cell. In the process of forming of CURD phase of metabolism inhibition by the above effectors the protective influence of tissue stress develops a result of cell reactivity decrease in response to the external damaging influences.

The place of the tissue stress in line of the unspecific adaptive reactions

The main feature of the tissue stress is its formation with participation of the tissuespecific effectors of intratissue intercellular interactions – comutons, chalones and contactins, which are produced by the cells of a tissue under a stressor’s influence. This distinguishes the tissue stress from the general adaptive syndrome, which is realized via hormones – effectors of interorgan interactions (see Stress (biological)). Regional (local) stress forms with participation of not one but several tissues making up an organ or a body part. This is why it can be believed that regional stress-reaction is realized with the participation of effectors of intraorgan intertissue interactions. Finally, the cell stress is realized via intracellular mechanisms, without any participation of intercellular interactions. In the latter case the CURD formation and synthesis of heat shock proteins act as “self-defense” mechanism of the cell.

Another distinctive feature of tissue stress is the principle of formation of its executive mechanism, the CURD, via tissuespecific self-damage of homologous tissue cells. Despite the fact that TAS, just as the cell stress, is realized via CURD, the TAS has a variety of features which distinguish it from the cell stress, the key one being the tissue-selectivity of CURD initiation under TAS effectors influence. In addition, under cell stress the cell protection is realized with CURD participation only via “passive” mechanism. It consists in the formation of the protective phase of this physiological reaction. Meanwhile, under tissue stress, its protective function may be carried out both the “passive” and “active” CURD-induced mechanisms. Thus, the cell stress mechanism is just one of the two instruments with which TAS protects the cells of homologous tissue. The third difference between tissue and cell stresses lies in ability of the former not only to increase but also to decrease the unspecific resistance of the cells. Meanwhile, the cell stress concept considers only the first possibility.

At the present moment, two physiological functions of tissue stress, which are realized in the process of participation of its adaptive mechanism, can be considered. One of them is expressed in an increase of cell specialized functions stability in the conditions of prolonged functional load. Another tissue stress function is to regulate homologous tissue cell mass in various physiological conditions.

Tissue stress function on homologous tissue cells specialized functions stability improvement

It is well known that only some part of tissue functional units participate in its cells specialized functions realization (Barcroft, 1937). Because of universality of this phenomenon it was named “the law of intermittent activity of functioning structures” (Kryshanovskii, 1973; Kryshanovskii, 1974). According to this law, functional units of actively functioning tissue (or cells) form two populations where one is in “intensive functioning” state and the other one – is in “resting” state. Thereat the “rest” is not a passive state since there active reparation of cellular structures occurs damaged in the course of specialized functions performing by cells. “Intermittent” pattern of tissue cells specialized functions realization is that the cells pass from one population to another when the tissue is in intensive functioning mode. In such a way the cells damaged in consequence of intensive functioning gain an offing to recover in “resting” population. Meanwhile, recovered cells pass from the “resting” population into “intensively functioning” one. It is safe to say that such organization of tissue functioning favors stability of its cells functions performance. Yet, the mechanisms which regulate cells passage from one population to another on intratissue level are unknown.

Considering the law of “intermittent activity of functioning structures” one can talk about two results of the TAS mechanism action on the cells of actively functioning tissue. In conditions where the TAS effector (effectors) forms CURD phase of metabolism stimulation one should expect an acceleration of reparative processes in the cells of “resting” population. Obviously that will promote accelerated recovery of such cells and their pass to intensively functioning cell population. In case if TAS mechanism forms the CURD phase of metabolism inhibition in intensively functioning cells population this will lead to cell signaling inhibition and promote cells “autonomy” from other external influences. Such autonomy may provoke an inhibition of cell’s specialized functions in mentioned population in case if they are stimulated by external regulatory influences. An inhibition of cells specialized functions by the TAS mechanism may promote defense of intensively functioning cells from self-damage and also their pass into the “resting” state. Thus, the properties of tissue stress executive mechanism – CURD – allow it to raise tissue functions stability in conditions of continuous intensive activity in many ways.

Tissue stress function on regulation of homologous tissue cell mass

According to the TAS concept, tissue stress possess the ability to regulate the cell mass of homologous tissue via executive mechanism described above – the CURD. As in the case of cells specialized functions regulation there are two ways of tissue-specific control of homologous tissue cell mass. These are cells unspecific resistance modulation and influencing the speed of physiological processes occurring in the cell.

Tissue stress mechanism able to control tissue cell mass influencing both its mitotic and apoptotic (see Apoptosis) activities tissue-specifically. In case if TAS effectors form CURD phase of metabolism stimulation one should expect acceleration of proliferative (see Proliferation) pool cells passage through mitotic cycle (MC). Herewith there will be also an acceleration of cells maturation and ageing. This will provoke an increase of both mitotic and apoptotic activity in tissue. On the contrary, formation of CURD phase of metabolism protective inhibition should result in opposite results – an inhibition of all mentioned processes and, as a result, to inhibition of both mitotic and apoptotic activities. One cannot exclude the possibility that tissue stress mechanism considered able to regulate apoptosis through inhibition of its energy-dependent stage. As concerns the modulation of cells unspecific resistance by tissue stress mechanism, this property of CURD allows to regulate cells entrance into MC as well as their entrance into apoptosis.

Regulation of tissue cell mass by the TAS mechanism can be carried out in two physiological regimes – ether by formation of “conservative” or “dynamic” phase of this adaptive reaction. TAS conservative phase is forming under the influence of “weak” unspecific external damaging or “load” influences on cells specialized functions. Here tissue stress provides intratissue adaptation by preservation of the existing cell population in the tissue. It is achieved by raise of cells unspecific resistance under the influence of tissue-specific self-damage of cells by TAS effectors. This prevents entrance of postmitotic cells both into MC and apoptosis. The TAS dynamic phase forms under “strong” external unspecific damaging or “loading” influences on cells specialized functions. According to TAS concept in dynamic phase of tissue stress a summation of damaging influence of stressor (stressors) with cells self-damage by TAS effectors occurs. This leads to stimulation of proliferation (see Proliferation) and to an increase of apoptotic activity (see Apoptosis) simultaneously. Thus, in above case adaptive function of tissue stress realizes by replacement of damaged, dying cells by descendents of cells more resistant to stressor(s) influence.

As is clear from the foregoing according the TAS concept tissue stress mechanism effect on homologous tissue cells is multifarious. It may protect them against the unspecific damaging influences as well as to increase stability of tissue specialized functions in the conditions of prolonged intensive functional activity. Simultaneously, the same mechanism performs intratissue control of cell mass of homologous tissue.

 

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