Category Archives: Cell biology and Genetics

– Cell cycle
– Cancer
– Bone remodeling.
– How blood glucose is regulated?

Neuroglia – The Other Cells of the Brain, with Animation.

The videos on this page can be downloaded upon purchase of a license on Alila Medical Media website. Click here!

A human brain contains billions of neurons. Neurons are probably the most important and best-known cells of the brain as they carry out the brain’s communication function. Less known are some trillions of support cells called glia, or glial cells. The glia may not be the stars of the show, but without them, neuron functions would be impossible.
The major types of glial cells in the brain include: oligodendrocytes, microglia, and astrocytes.
Oligodendrocytes are specialized cells with arm-like processes that wrap tightly around axons of neurons to form the myelin sheath. The myelin sheath acts like an electrical insulator around a wire. It helps to speed up the electrical signals that travel down an axon. Without oligodendrocytes, an action potential would propagate 30 times slower!
Microglia are special macrophages found only in the central nervous system. They wander through the brain tissue and phagocytize dead, injured cells and foreign invaders. High concentrations of microglia are an indication of infection, trauma or stroke.
Astrocytes are the most abundant and functionally diverse glia.
These star-shaped glial cells provide supportive frameworks to hold neurons in place. They provide neuron with nutrients such as lactate. They also produce growth factors that promote neuron growth and synapse formation. There is growing evidence that astrocytes can alter how a neuron is built by directing where to make synapses or dendritic spines.
Through their numerous processes, known as perivascular feet, astrocytes induce the endothelial cells of blood vessels to form tight junctions. These tight junctions are the basis of the blood brain barrier that restricts the passage of certain substances from the bloodstream to the brain tissue.
Astrocytes help to maintain the chemical composition of the extracellular fluid. They express membrane transporters for several neurotransmitters such as glutamate, ATP and GABA, and help to remove them from synaptic spaces.
Astrocytes also absorb potassium ions released by neurons at synapses. This helps to regulate potassium concentrations in the extracellular space. Abnormal accumulation of extracellular potassium is known to result in epileptic neuronal activity.
Another function of astrocytes is to form scar tissues to replace damaged tissues.
Recently, it has been shown that astrocytes can also communicate electrically with neurons and modify the signals they send and receive. In a manner similar to neurons, astrocytes can release transmitters, called gliotransmitters, upon stimulation. These open up a possibility that astrocytes maybe much more involved in the communication functions of the brain than we currently believe.

Clinical implication
From a clinical viewpoint, neurons have little capacity for renewal and therefore rarely form tumors. On the contrary, glial cells are capable of dividing throughout life and are the primary source of brain tumors.

Protein Synthesis – Translation

Below is a narrated animation of prokaryotic translation. Click here to license this video on Alila Medical Media website.

Translation is the process of making polypeptide (protein) from the messenger RNA (mRNA).

The translation process involves the following components:
– mRNA or messenger RNA containing the genetic information to be translated.
– tRNA or transfer RNA bringing in the amino acids – the building blocks of the protein.
– Ribosome – the machine that performs the translation. The ribosome has two subunits: small and large.
– Several initiation factors (IFs), elongation factors (EFs) and release factors (RFs). These factors assist with initiation, elongation and termination of the process, respectively.

Steps of the translation process

Initiation: The small ribosomal subunit binds to the initiator tRNA carrying the initiator amino acid methionine (fMet). In eukaryotes, this complex then attaches to the cap structure at the 5’ end of an mRNA and scans for the start codon AUG. The process is mediated by several initiation factors. This is cap-dependent initiation. In some cases, the initiation complex binds to an internal ribosome entry sites (IRES) on the mRNA – this is cap-independent initiation. The rest of the events remain the same. In prokaryotes, the initiation complex recognizes and binds to a a purine-rich region – the Shine Dalgarno sequence – upstream of the AUG initiation codon.

At the start codon, the large ribosomal subunit joins the complex and all initiation factors are released. The ribosome has three sites: the A-site is the entry site for new tRNA charged with amino-acid or aminoacyl-tRNA; the P-site is occupied by peptidyl-tRNA – the tRNA that carries the growing polypeptide chain; the E-site is the exit site for the tRNA after it’s done delivering the amino acid. The initiator tRNA is positioned in the P-site.

Fig. 1: Translation initiation (eukaryotic, cap-dependent). Click on image to see it on Alila Medical Media website where the image is also available for licensing (together with other related images and videos).

Elongation: A new tRNA carrying an amino acid enters the A-site of the ribosome. On the ribosome, the anticodon of the incoming tRNA is matched against the mRNA codon positioned in the A-site. During this proof-reading, tRNA with incorrect anticodons are rejected and replaced by new tRNA that are again checked. When the right aminoacyl-tRNA enters the A-site, a peptide bond is made between the two now-adjacent amino-acids. As the peptide bond is formed, the tRNA in the P-site releases the amino-acids onto the tRNA in the A-site and becomes empty. At the same time, the ribosome moves one triplet forward on the mRNA. As a result, the empty tRNA is now in the E-site and the peptidyl tRNA moves to the P-site. The A-site is now unoccupied and is ready to accept a new tRNA. The cycle is repeated until the ribosome reaches a stop codon.

Fig. 2: Translation elongation. Click on image to see it on Alila Medical Media website where the image is also available for licensing (together with other related images and videos).

Termination: Termination happens when one of the three stop codons is positioned in the A-site. No tRNA can fit in the A-site at that point as there are no tRNA that match that sequence. Instead, these codons are recognized by a protein, a release factor. Binding of the release factor catalyzes the cleavage of the bond between the polypeptide and the tRNA. The polypeptide is released from the ribosome. The ribosome is disassociated into subunits and is ready for a new round of translation. The newly made polypeptide usually requires additional modifications and folding before it can become an active protein.

Fig. 3: Translation termination. Click on image to see it on Alila Medical Media website where the image is also available for licensing (together with other related images and videos).

Cancer

The videos on this page can be downloaded upon purchase of a license on Alila Medical Media website. Click here!

The number of cells in a tissue is determined by the balance between cell division and cell death. Uncontrollable cell division leads to formation of abnormal growths called tumors. Tumors can be benign or malignant. Benign tumors are slow-growing and constrained by surrounding connective tissue so they do not spread to other organs. They can still be harmful or even kill by pressing on nearby nerves, brain tissue or blood vessels. Examples of benign tumor include pituitary tumors which may press on optic nerves and cause loss of vision. Cancers are malignant tumors – tumors that can spread beyond of the limit of original organ where it comes from and to other organs of the body.

How cancer starts

Cancer starts from a damage in the DNA of a cell. This DNA damage is called mutation. Mutations happen when the cell duplicates its DNA prior to cell division and makes mistakes. These damages are usually detected and repaired before the cell can divide but sometimes, some of them may be ignored and transferred to daughter cells.

If the mutation is located in one of many genes that control the cell cycle, it may affect the regulation of cell cycle in the cell carrying it, and make the cell divide faster than it supposed to. Usually, one mutation is not enough to cause cancer, but as it makes the cell cycle control less reliable, many more DNA damages/mutations would go unnoticed. Cancer is usually the result of accumulation of many mutations of genes involved in cell cycle control and DNA repair. This commonly happens over a long period of time, over many rounds of cell divisions, and this explains why cancers are more common in older people.

Fig. 1 Cancer cells reproduce to from tumor. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Some people are said to be predisposed to cancer. This is because they are born with a mutation that makes them more likely to develop a certain type of cancer. This mutation alone is not enough to cause cancer but it starts the process of making cells cancerous. The person carrying it is one step further down the road towards developing a cancer than others who do not have the mutation.

Genes that are mutated in cancer

Three main classes of genes that are found mutated in cancers:

Proto-oncogenes – when mutated become oncogenes. Most cells do not divide until a growth factor binds to a receptor on its surface and instruct it to do so. Growth factor binding activates a cascade of events preparing the cell for division. Proto-oncogenes encode for normal growth factors and growth factor receptors. Oncogenes encode for abnormal versions of these. These malfunctional growth factors and receptors instruct the cells to divide non-stop causing cancer. A well known example of oncogene is ras, which encodes for a mutated growth factor receptor.

Tumor suppressors (TS) genes – these encode for cell cycle inhibitors, a class of molecules that prevent the progression of the cell cycle. Many of these arrest the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes. A famous TS gene is p53, which is found mutated in majority of cancers including colon, brain, breast, lung cancers and leukemia.

DNA repair genes – these encode for enzymes that repair damage in DNA before the cell can divide. Mutations in these genes lead to accumulation of mutations that eventually make the cell cancerous.

How cancer spreads

Cancer cells do not stick together like normal cells, they move and invade nearby tissues, organs, this is local spread. They may also spread to further away organs by means of blood and lymph circulation, this is systemic spread. Metastasis is the spreading of cancers to non-adjacent organs. Cancer cells from the original tumor (primary cancer) can break out and maybe taken up by a blood or a lymph vessel for a ride throughout the body. They can then squeeze out from the vessels into other tissues and start a new tumor growth in the new location which will become secondary cancer.

Fig. 2 : Cancer cells squeeze through the wall of blood and lymph capillary. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Where do cancers usually spread and why?

While travelling in the bloodstream, cancer cell usually stops at the first place where the vessel getting so narrow that it gets stuck. As blood flow from most organs goes to the capillaries of the lungs, this is where cancers spread the most. Lungs are indeed the most common site of secondary cancers.

Fig. 3 : Primary cancer from the pancreas metastases to the lungs through the bloodstream. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Likewise, while travelling in the lymphatic system, cancer cells commonly get stuck in nearest lymph nodes, where the vessels get narrower. This is the reason why surgeons usually remove nearby lymph nodes when removing tumors.

Cell cycle

Most cells divide periodically to give rise to two daughter cells. A cell cycle covers a period of time from one cell division to the next.

Phases of cell cycle

– First gap phase – G1 phase – cell grows in size and prepares for DNA replication. G1 checkpoint (see below) makes sure everything is ready for DNA replication. This is also the period where the cells carry out their normal metabolic roles for the body.

– Synthesis phase – S phase – DNA replication occurs, the cell makes a second, identical set of DNA molecules. It now has two sets, ready to distribute to the two daughter cells.

– Second gap phase – G2 phase – preparation for cell division, cell synthesizes proteins/enzymes that are necessary for mitosis. G2 checkpoint (see below) makes sure the cell is ready for division.

– Proper cell division – M phase – mitosis phase where the mother cell is split into two daughter cells by the process of mitosis. Mitosis has four phases on its own : prophase, metaphase, anaphase and telophase (commonly with cytokinesis).

Fig. 1 : A typical cell cycle with four phases. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

The G1, G2 and S phases are together called interphase – the time in between M phases. The length of cell cycle varies greatly from one cell type to another with the length of G1 phase being most variable.

G0 (G zero) phase

In an adult multicellular organism, it’s very common for cells to stop dividing permanently or temporary for a certain period of time. Such cells are said to be in G0 phase (resting phase), or to be quiescent. They usually enter G0 phase from G1 phase (Fig. 2). Fully differentiated skeletal muscle cells and neurons are post-mitotic and stay in G0 for the rest of their life. Some other cells can be stimulated to get back to G1 when needed (e.g. liver cells). Finally, there are cells that never enter G0 and continue dividing for life (e.g. epithelial cells).

Fig. 2 : A cell cycle diagram showing exit to G0. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Cell cycle checkpoints

Checkpoints are control mechanisms to ensure that cell division proceeds with highest accuracy. Before going into the next phase, the cell has to check if everything is ready, scan for DNA damage and activate repair if needed. If the cell is not ready, cell cycle will be arrested. This is to ensure that damaged or incomplete DNA molecules are not passed onto daughter cells.

There are three main checkpoints in the cell cycle:

– G1 checkpoint ( also called restriction point in animal cell, or start point in yeast) is located at the end of G1 phase, before the entrance to S phase. This is the point when the cell needs to make a decision to divide or not depending on the environmental factors. The cell may proceed to cell division (to S phase), delay division waiting for more signals (stay in G1), or enter resting phase (to G0 phase).

– G2 checkpoint is located at the end of G2 phase, before commitment to M phase. Here the cell needs to check if everything is ready for mitosis. Most importantly, it has to check for any DNA damages that may have occurred during DNA synthesis (S phase). If damages are detected, cell cycle will be arrested at this point.

– Metaphase checkpoint (spindle checkpoint) is located in metaphase, before the onset of anaphase. This is to make sure that ALL the chromosomes are properly aligned at the metaphase plate before the sister chromatids can be pulled apart in anaphase. If a chromosome is “late” to come to its position, the metaphase will be arrested waiting for it. This is how the cell ensures that the two daughter cells will have exactly the same set of chromosomes. Failure of this would result in a daughter cell with an extra chromosome and the other missing a chromosome, a situation that is deleterious for both.

Molecular regulators of cell cycle

Cyclins and cyclin-dependent kinases (CDKs) form cyclin-CDK complexes that determine the progression of cell cycle through different phases. Cyclins are regulatory subunits of the complexes and are expressed only at specific stages of cell cycle. CDKs are catalytic subunits of the complexes and are activated by binding to cyclins. Upon binding to a cyclin, CDK acquires ability to phosphorylate target proteins. CDKs are constitutively expressed. Combination of different CDKs to different cyclins determine substrate specificity of the complexes.

Inhibitors of cell cycle or tumor suppressors – a class of molecules that prevent the progression of the cell cycle. Many of these arrest the cell cycle in G1 phase by binding to and inactivating cyclin-CDK complexes.

Regulation of cell cycle and cancer

The number of cells in a tissue is determined by the balance between cell division and cell death. The proportion of cells actively dividing versus those in resting (G0) phase plays an important role and must be strictly controlled. Disregulation of cell cycle would result in uncontrollable cell division and formation of abnormal growths called tumors. Tumors that can spread to other organs are cancers. Cancerous cells are characterized by an inability to stop diving and to enter resting phase.

Bone remodeling

Bone remodeling (bone metabolism) is the process of removal of old bone tissue and formation of a new one.

Functions of bone remodeling

– Renewal of bone tissue to prevent accumulation of old bone with multiple micro-damages.

– Repair of small injuries : In response to small fractures, the damaged tissue is removed and new bone matrix is formed to replace it.

– Adjustment of bone architecture to meet changing mechanical needs: new bone matrix is deposited where needed, old bone tissue is removed elsewhere.

– Role in maintenance of calcium homeostasis of blood plasma.

Bone remodeling process

Bone remodeling involves the removal of bone tissue by osteoclasts followed by the formation of new bone matrix deposited and mineralized by osteoblasts (Fig. 1).

Fig. 1: Bone remodeling cycle: resorption, reversal and formation. See text for details. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Bone resorption : removal of old bone tissue by osteoclasts. Osteoclasts are bone-dissolving cells. They derive from hematopoietic stem cells and are product of fusion of several cell precursors. Because of this, osteoclasts are unusually large and multinuclear. Osteoclast resembles an octopus crawling on the bone surface due to the presence of a ruffled border – multiple infoldings of plasma membrane – served to increase its surface area. They also have a foamy appearance as they contain lots of lysosomes.

Reversal: Mononuclear cells (monocytes, macrophages) clean up the debris on bone surface.

New bone formation : Recruitment of pre-osteoblasts to the surface, these mature to become osteoblasts. Osteoblasts are bone – forming cells. They synthesize the organic matter of bone matrix (osteoid). Osteoid mineralized and becomes new bone.

Osteocytes are former osteoblasts that have been trapped in the bone matrix they deposited. They can no longer synthesize bone matrix and instead serve as mechanical sensors. When they detect a strain in a bone, they communicate with the osteoblasts on the bone surface. These latter would deposit bone matrix where needed in response.

Bone modeling versus Bone remodeling

Bone modeling is the process in which bones change their overall shape to adapt to physiological and mechanical changes. In bone modeling, the two sub-processes of bone resorption and bone formation are less coordinated, i.e. bone resorption may happen without subsequent new bone formation and vice versa: new bone formation may happen without old bone being removed. Bone modeling is more frequent in growing children while bone remodeling is more frequent in adults.

Disorders of bone metabolism

Bone resorption and formation must be in balance to maintain healthy bone metabolism. When bone resorption overtakes new bone formation, bone loss – osteoporosis – may result (Fig. 2). Osteoporosis (or porous bone) is very common in older adults, especially in post-menopause women. This condition usually affects all the bones in the body.

Fig. 2: Bone loss in osteoporosis (right panel) compared to normal bone tissue (left). Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Another disorder of bone remodeling is Paget’s disease of bone (osteitis deformans). This condition is characterized by larger and denser but weaker bones. Paget’s disease typically is localized to just a few bones. The pelvis, lower spine and long bones of the legs are the most commonly affected.

> See all Orthopedic topics

How blood glucose is regulated?

Blood glucose levels are regulated by the cells of the pancreatic islets (islets of Langerhans). When glucose level is high (e.g. after a meal), beta cells of the islet release insulin into the bloodstream. Insulin stimulates target cells (e.g. muscle cells) to use glucose as energy source. Insulin also induces liver cells to store glucose in the form of glycogen (this process is called glycogenesis). When glucose levels fall (e.g. in the morning before breakfast), another hormone called glucagon is released by alpha cells of the pancreatic islets. Glucagon acts on liver cells to convert glycogen back to glucose and release it into the bloodstream (this process is called glycogenolysis).

How glucose induces insulin release in beta cells?

Shortly after a meal, level of glucose in the blood is up. High glucose level stimulates beta cells to secrete insulin into the bloodstream (Fig. 1 and 2).

Fig. 1: Anatomy of a pancreatic islet (islet of Langerhans): beta cells = blue, alpha cells = red; and an enlarged beta cell (lower panel). Glucose enters beta cell and stimulates exocytosis of vesicles containing insulin. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Glucose enters beta cell through glucose transporter 2 – GLUT2. Increased intake of glucose => increased production of ATP => ATP/ADP ratio is up => ATP-sensitive potassium channel closed => depolarization of cell membrane => voltage-gated calcium channel opens => increased calcium inside the cell => insulin granule exocytosis.

Fig. 2: Chain of events that lead to secretion of insulin from beta cells. See text for details. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

How insulin induces glucose uptake in target cells?

Insulin and glucose travel in bloodstream to reach target organs (e.g. muscles, liver,..). In target organs, insulin induces cells to take up glucose. Insulin binds to insulin receptor on target cell => phosphorylation of cytoplasmic domain of receptor => a cascade of signaling events brings the GLUT4 (glucose transporter 4) to the membrane of the cell => glucose enters target cell through GLUT4.

Fig. 3: Insulin signaling in target cell. See text fior details. Click on image to see a larger version on Alila Medical Media website where the image is also available for licensing.

Glucagon

Glucagon is secreted into the bloodstream in response to hypoglycemia – low blood sugar. Glucagon has the opposite effect of insulin, its action increases blood glucose level. Glucagon secretion from alpha cells is suppressed by high level of glucose. Low concentration of glucose => increase level of glucagon. Glucagon stimulates breakdown of glucogen stored in liver cells (hepatocytes) and release of glucose into the blood.

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