Calcium Wave During Fertilization

Signaling III / Metabolic Control I Lecture


Calmodulin

Calmodulin (CaM) (an abbreviation for CALcium-MODULated proteIN) is a calcium-binding messenger protein expressed in all eukaryotic cells. CaM is a multifunctional intermediate messenger protein that transduces calcium signals by binding calcium ions and then modifying its interactions with various target proteins.


Function

CaM mediates many crucial processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and the immune response. CaM is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes. Many of the proteins that CaM binds are unable to bind calcium themselves, and as such use CaM as a calcium sensor and signal transducer. CaM can also make use of the calcium stores in the endoplasmic reticulum, and the sarcoplasmic reticulum. CaM can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which has potential to modulate its actions.

Mechanism

Up to four calcium ions are bound by calmodulin via its four EF hand motifs. EF hands supply an electronegative environment for ion coordination. After calcium binding, hydrophobic methyl groups from methionine residues become exposed on the protein via conformational change. This presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices (BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The flexibility of Calmodulin's hinged region allows the molecule to "wrap around" its target. This property allows it to tightly bind to a wide range of different target proteins.

Crawling Actin

Tumor Neovascularization


Neuron

The complexity and diversity in nervous systems is dependent on the interconnections between neurons, which rely on a limited number of different signals transmitted within the neurons to other neurons or to muscles and glands. The signals are produced and propagated by chemical ions that produce an electrical charge that moves along the neuron.

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Neurons exist in a number of different shapes and sizes and can be classified by their morphology and function. The anatomist Camillo Golgi grouped neurons into two types; type I with long axons used to move signals over long distances and type II without axons. type I cells can be further divided by where the cell body or soma is located. The basic morphology of type I neurons, represented by spinal motor neurons, consists of a cell body called the soma and a long thin axon which is covered by the myelin sheath. Around the cell body is a branching dendritic tree that receives signals from other neurons. The end of the axon has branching terminals (axon terminal) that release transmitter substances into a gap called the synaptic cleft between the terminals and the dendrites of the next neuron.
The anatomy and the properties of the surface membrane determine the behavior of a neuron. The surface membrane is not uniform over the entire length of a neuron, but is modified in specific areas: some regions secrete transmitter substances while other areas respond to the transmitter. Other areas of the neuron membrane have passive electrical properties that effect capacitance and resistance. Within the neuron membrane there are gated ion channels that vary in type, including fast response sodium channels that are voltage-gated and are used to send rapid signals.
Neurons communicate by chemical and electrical synapses in a process known as synaptic transmission. The fundamental process that triggers synaptic transmission is the action potential, a propagating electrical signal that is generated by exploiting the electrically excitable membrane of the neuron. This is also known as a wave of depolarization.
Fully differentiated neurons are permanently amitotic; however, recent research shows that additional neurons throughout the brain can originate from neural stem cells found in high concentrations in (but throughout the brain) the subventricular zone and subgranular zone through the process of neurogenesis.

Evolution of cancer stem cells Lecture


TrK Receptor Animation

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signal cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.




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The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system. The binding of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
The abbreviation trk (often pronounced 'track') stands for tropomyosin-receptor-kinase (and not tyrosine kinase nor tropomyosin-related kinase, as has been commonly mistaken).
The family of Trk receptors is named for the oncogene trk, whose identifical led to the discovery of its first member, TrkA. trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas . The oncogene was generated by a mutation in chromosome 1 that resulted in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor . Normal Trk receptors do not contain amino acid or DNA sequences related to tropomyosin.
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptors types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse of biological responses.
Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
TrkA
TrkA has the highest affinity to the binding nerve growth factor (NGF). NGF is important in both local and nuclear actions, regulating growth cones, motility, and expression of genes encoding the biosynthesis enzymes for neurotransmitters. Nocireceptive sensory neurons express mostly trkA and not trkB or trkC.
TrkB
TrkB has the highest affinity to the binding brain-derived neurotrophic factor (BDNF) and NT-4. BDNF is growth factor that has important roles in the survival and function of neurons in the central nervous system. The binding of BDNF to TrkB receptor causes many intercellular cascades be activated, which regulate neuronal development and plasticity, long-term potentiation, and apoptosis.
Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease.
TrkC is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent.) TrkC is mostly expressed by proprioceptive sensory neurons. The axons of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.
Essential roles in differentiation and function Precursor cell survival and proliferation
Numerous studies, both in vivo and in vitro, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system. TrkA that expresses NGF not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
Control of target innervation
Each of the neurotrophins mentioned above[vague] promotes neurite outgrowth. NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF.[vague] NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.
Sensory neuron function
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties. Both NT-3 and BDNF are important in the regulation and development of synapses formed between afferent neurons and motor neurons.Increased NT-3/trkC binding results in larger monosynaptic excitatory postsynaptic potentials (EPSPs) and reduced polysynaptic components. On the other hand, increased NT-3 binding to trkB to BDNF[vague] has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.
Formation of ocular dominance column
In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleus (LGN) and terminate in separate layers of striate cortex. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese axons that terminate in layer IV of the striate cortex result in ocular dominance columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet.Previous studies with cat model has shown that monocular deprivation occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation.Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.

Nanotechnology in Cancer

Nanotechnology offers the unprecedented and paradigm-changing opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the earliest stages of the cancer process. Through the concerted development of nanoscale devices or devices with nanoscale materials and components, the NCI Alliance for Nanotechnology in Cancer will facilitate their integration within the existing cancer research infrastructure. The Alliance will bring enabling technologies for:




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  • Imaging agents and diagnostics that will allow clinicians to detect cancer in its earliest stages
  • Systems that will provide real-time assessments of therapeutic and surgical efficacy for accelerating clinical translation
  • Multifunctional, targeted devices capable of bypassing biological barriers to deliver multiple therapeutic agents directly to cancer cells and those tissues in the microenvironment that play a critical role in the growth and metastasis of cancer
  • Agents that can monitor predictive molecular changes and prevent precancerous cells from becoming malignant
  • Novel methods to manage the symptoms of cancer that adversely impact quality of life
  • Research tools that will enable rapid identification of new targets for clinical development and predict drug resistance


Why Nanotechnology in Cancer?
Nanoscale devices are somewhere from one hundred to ten thousand times smaller than human cells. They are similar in size to large biological molecules ("biomolecules") such as enzymes and receptors. As an example, hemoglobin, the molecule that carries oxygen in red blood cells, is approximately 5 nanometers in diameter. Nanoscale devices smaller than 50 nanometers can easily enter most cells, while those smaller than 20 nanometers can move out of blood vessels as they circulate through the body.

Because of their small size, nanoscale devices can readily interact with biomolecules on both the surface of cells and inside of cells. By gaining access to so many areas of the body, they have the potential to detect disease and deliver treatment in ways unimagined before now. And since biological processes, including events that lead to cancer, occur at the nanoscale at and inside cells, nanotechnology offers a wealth of tools that are providing cancer researchers with new and innovative ways to diagnose and treat cancer.

Nanotechnologies

Work is currently being done to find ways to safely move these new research tools into clinical practice. Today, cancer-related nanotechnology is proceeding on two main fronts: laboratory-based diagnostics and in vivo diagnostics and therapeutics.
Nanotechnology and Diagnostics

Nanodevices can provide rapid and sensitive detection of cancer-related molecules by enabling scientists to detect molecular changes even when they occur only in a small percentage of cells.

Nanotechnology and Cancer Therapy

Nanoscale devices have the potential to radically change cancer therapy for the better and to dramatically increase the number of highly effective therapeutic agents. Nanoscale constructs can serve as customizable, targeted drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells, greatly reducing or eliminating the often unpalatable side effects that accompany many current cancer therapies.

Ref:http://nano.cancer.gov/resource_center/nano_critical.asp

Leucine Zipper

A leucine zipper, (leucine scissors), is a super secondary structural motif found in proteins that creates adhesion forces in parallel alpha helices. It is a common dimerization domain found in some proteins involved in regulating gene expression.
Structure
The main feature of the leucine zipper domain is the predominance of the common amino acid leucine at the d position of the heptad repeat. Leucine zippers were first identified by sequence alignment of certain transcription factors which identified a common pattern of leucines every seven amino acids. These leucines were later shown to form the hydrophobic core of a coiled coil.
 Leucine Zipper Animation

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FOS and AP1 Bound to DNA
Each half of a leucine zipper consists of a short alpha-helix with a leucine residue at every seventh position. The standard 3.6 residues per turn alpha-helix structure changes slightly to become a 3.5 residues per turn alpha-helix. Known also as the heptat repeat, one leucine comes in direct contact with another leucine on the other strand every second turn.
The bZip family of transcription factors consist of a basic region which interacts with the major groove of a DNA molecule through hydrogen bonding, and a hydrophobic leucine zipper region which is responsible for dimerization.
Leucine zipper regulatory proteins include c-fos and c-jun (the AP1 transcription factor), important regulators of normal development. If they are overproduced or mutated in a vital area, they may generate cancer. These proteins interact with the DNA as dimers (homo- or hetero-) and are also called basic zipper proteins (bZips).

HIV Viral Entry

HIV enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

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Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120 binds to integrin α4β7 activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1 and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

Once HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease and protease, are injected into the cell. During the microtubule based transport to the nucleus, the viral single strand RNA genome is transcribed into double strand DNA, which is then integrated into a host chromosome.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells once the virus has been captured in the mucosa by DCs.

Mouse Genotyping Video


video

Ovarian Cancer and Treatment

Ovarian cancer is a cancerous growth arising from an ovary. Although ovarian cancer is known to occur in many species, the majority of the medical literature and the focus of this article is on ovarian cancer in humans.


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Ovarian cancer most commonly forms in the lining of the ovary (resulting in epithelial ovarian cancer) or in the egg cells (resulting in a germ cell tumor). Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of death from gynecological cancer. A woman has a lifetime risk of ovarian cancer of around 1.5%, which makes it the second most common gynecologic malignancy (the first being breast cancer).

Ovarian cancer has been named 'the silent killer' because it frequently causes non-specific symptoms, which contribute to diagnostic delay, diagnosis in a late stage and a poor prognosis. Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid in the abdominal cavity (this is called ascites).

Ovarian cancer affects over 64,000 women worldwide every year. Starting in the ovaries, the tumor often remains undetected till it reaches the late stage Leaving patient with poor prognosis.
Ovarian cancer tumors seven antigen called Ca125 are also present on the surface of the tumor itself. It is the responsibility of the body's first line of defense "dendritic cell" to recognize Ca125 antigen has harmful and take action. However the problem with CA125 and cancer in general is that dendritic cells doesn't recognize the cancer antigens as harmful and fail to take action against tumor. This is called tolerance.

OVEREXMAb an monoclonal antibody and a lead candidate drug seeks to break tolerance by re-training the body's immune system and teaching it to find it CA125 antigen and associated tumors. OVEREXS antibody is derived from mouse cells, and it is designed to target and bind to exclusively free-floating Ca1 25 antigen.
Dendritic cells are hardwired to engulf foreign proteins such as mouse antibodies and treat them potentially harmful. Because of this when antibody binds to free-floating Ca125 antigen the whole complex is recognized as being “foreign bodies” by dendritic cells for taking action.

Once the complex is engulfed the dendritic cells break down the key protein from the unit and presenting protein in all parts on the cell surface, so that T Cell get activated. It is from here that killer T-Cells are alerted, and reprogrammed to fight the internal threat. Once activated these T Cells will replicate creating more activated Tcells.Any tumor cells expressing CA125 antigen are then targeted for destruction.

Threonine

Threonine (abbreviated as Thr or T) is an α-amino acid with the chemical formula HO2CCH(NH2)CH(OH)CH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar. Together with serine and tyrosine, threonine is one of three proteinogenic amino acids bearing an alcohol group.

The threonine residue is susceptible to numerous posttranslational modifications. The hydroxy side chain can undergo O-linked glycosylation. In addition, threonine residues undergo phosphorylation through the action of a threonine kinase. In its phosphorylated form, it can be referred to as phosphothreonine.



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Allo-threonine
With two chiral centers, threonine can exist in four possible stereoisomers, or two possible diastereomers of L-threonine. However, the name L-threonine is used for one single enantiomer, (2S,3R)-2-amino-3-hydroxybutanoic acid. The second diastereomer (2S,3S), which is rarely present in nature, is called L-allo-threonine.

Biosynthesis
As an essential amino acid, threonine is not synthesized in humans, hence we must ingest threonine in the form of threonine-containing proteins. In plants and microorganisms, threonine is synthesized from aspartic acid via α-aspartyl-semialdehyde and homoserine. Homoserine undergoes O-phosphorylation; this phosphate ester undergoes hydrolysis concomitant with relocation of the OH group.[2] Enzymes involved in a typical biosynthesis of threonine include:

aspartokinase
α-aspartate semialdehyde dehydrogenase
homoserine dehydrogenase
homoserine kinase
threonine synthase.

Metabolism
Threonine is metabolized in two ways:

It is converted to pyruvate via threonine dehydrogenase. An intermediate in this pathway can undergo thiolysis with CoA to produce Acetyl-CoA and glycine.
In humans, it is converted to alpha-ketobutyrate in a less common pathway via the enzyme serine dehydratase, and thereby enters the pathway leading to succinyl-CoA.

Sources
Foods high in threonine include cottage cheese, poultry, fish, meat, lentils, and sesame seeds.[citation needed]

Racemic threonine can be prepared from crotonic acid by alpha-functionalization using mercury(II) acetate.

Threonine. (2009, February 13). In Wikipedia, The Free Encyclopedia. Retrieved 08:47, February 17, 2009, from http://en.wikipedia.org/w/index.php?title=Threonine&oldid=270547548

Cell Cycle Checkpoints


Oncogenes

An oncogene is a protein-encoding gene which, when deregulated, participates in the onset and development of cancer. Genetic mutations resulting in the activation of oncogenes increase the chance that a normal cell will develop into a tumor cell. Oncogenes are figuratively thought to be in a perpetual tug-of-war with tumor suppressor genes which act to prevent DNA damage and keep the cell's activities under control. There is much evidence to support the notion that loss of tumor suppressors or gain of oncogenes can lead to cancer.

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Many cells normally undergo an apoptosis program. In the presence of an activated oncogene, disorderly survival and proliferation can be observed.[1] Most oncogenes require an additional step, such as mutations in another gene, or environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of oncogenes have been identified in human cancer. Many new cancer drugs target those DNA sequences and their products.

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene.[5] Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK.

Proto-oncogene
A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene.Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK.

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Allergies & IgE Activation

Allergies are abnormal immune responses to allergens like pollen grains, dust, moulds and foodstuffs. Allergens cause abnormal production of immunoglobulin E (IgE). When the antigen makes contact with some part of the body, it is taken up, processed by Antigen Presenting Cell (APC) and presented on a Class II MHC to Helper cells. In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in the T helper cells. These T helper cells produce cytokines which stimulate B-cells to produce large amount of IgE, which circulates in the blood and binds to an IgE-specific receptor on the surface of mast cells and basophils. During second exposure, antigen binds to the IgE antibodies on the mast cells, which undergo degranulation to release histamine and other inflammatory chemical mediators into the surrounding tissue causing symptoms like Nasal Stuffyness, Sneezing, Runny nose, Watery eyes and mucous discharge. This animation delineates the process of immune response on encounter with an allergen.

Monoclonal antibodies against flu