Gastroesophageal reflux disease(GERD)

Gastroesophageal reflux disease (American English and Canadian English) or Gastro-oesophageal reflux disease (British English, Hiberno-English, Australian English, New Zealand English, South African English) and abbreviated to either GERD or GORD is defined as chronic symptoms or mucosal damage produced by the abnormal reflux in the esophagus.

This is commonly due to transient or permanent changes in the barrier between the esophagus and the stomach. This can be due to incompetence of the cardia, transient cardia relaxation, impaired expulsion of gastric reflux from the esophagus, or a hiatus hernia.



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Symptoms
Adults

Heartburn is the major symptom of acid in the esophagus, characterized by burning discomfort behind the breastbone (sternum). Findings in GERD include esophagitis (reflux esophagitis) — inflammatory changes in the esophageal lining (mucosa) —, strictures, difficulty swallowing (dysphagia), and chronic chest pain. Patients may have only one of those symptoms. Typical GERD symptoms include cough, hoarseness, voice changes, chronic ear ache, burning chest pains, nausea or sinusitis. GERD complications include stricture formation, Barrett's esophagus, esophageal spasms, esophageal ulcers, and possibly even lead to esophageal cancer, especially in adults over 60 years old.

Occasional heartburn is common but does not necessarily mean one has GERD. Patients with heartburn symptoms more than once a week are at risk of developing GERD. A hiatal hernia is usually asymptomatic, but the presence of a hiatal hernia is a risk factor for developing GERD.

Children

GERD may be difficult to detect in infants and children. Symptoms may vary from typical adult symptoms. GERD in children may cause repeated vomiting, effortless spitting up, coughing, and other respiratory problems. Inconsolable crying, failure to gain adequate weight, refusing food, bad breath, and belching or burping are also common. Children may have one symptom or many — no single symptom is universal in all children with GERD.

It is estimated that of the approximately 4 million babies born in the U.S. each year, up to 35% of them may have difficulties with reflux in the first few months of their life. Most of those children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition.

Babies' immature digestive systems are usually the cause, and most infants stop having acid reflux by the time they reach their first birthday. Some children do not outgrow acid reflux, however, and continue to have it into their teen years. Children who have had heartburn that does not seem to go away, or any other GERD symptoms for a while, should talk to their parents and visit their doctor.


Diagnosis
A detailed history taking is vital to the diagnosis. Useful investigations may include barium swallow X-rays, esophageal manometry, 24-hour esophageal pH monitoring and Esophagogastroduodenoscopy (EGD). In general, an EGD is done when the patient does not respond well to treatment, or has alarm symptoms including: dysphagia, anemia, blood in the stool (detected chemically), wheezing, weight loss, or voice changes. Some physicians advocate once-in-a-lifetime endoscopy for patients with longstanding GERD, to evaluate the possible presence of Barrett's esophagus, a precursor lesion for esophageal adenocarcinoma.

Esophagogastroduodenoscopy (EGD) (a form of endoscopy) involves insertion of a thin scope through the mouth and throat into the esophagus and stomach (often while the patient is sedated) in order to assess the internal surfaces of the esophagus, stomach, and duodenum.

Biopsies can be performed during gastroscopy and these may show:

  • Edema and basal hyperplasia (non-specific inflammatory changes)
  • Lymphocytic inflammation (non-specific)
  • Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis)
  • Eosinophilic inflammation (usually due to reflux)
  • Goblet cell intestinal metaplasia or Barretts esophagus.
  • Elongation of the papillae
  • Thinning of the squamous cell layer
  • Dysplasia or pre-cancer.
  • Carcinoma.

Reflux changes may be non-erosive in nature, leading to the entity non-erosive reflux disease.

What is Gout


Gout is caused by buildup of uric acid,Uric acid crystalls travel and accumulate in the joints,in specially in feet and legs causing pain in the legs,crystals of monosodium urate or uric acid are deposited on the articular cartilage of joints, tendons and surrounding tissues. These crystals cause inflammation and pain, both severe. If unchecked, the crystals form tophi, which can cause significant tissue damage. Gout results from a combination of elevated concentrations of uric acid and overall acidity in the bloodstream. In isolation, neither elevated uric acid (hyperuricemia) nor acidity is normally sufficient to cause gout.

  Subscribe in a reader Signs and symptoms
Gout is characterized by excruciating, sudden, unexpected, burning pain, as well as swelling, redness, warmth, and stiffness in the affected joint. This occurs commonly in men in their toes but can appear in other parts of the body and affects women as well. Low-grade fever may also be present. The patient usually suffers from two sources of pain. The crystals inside the joint cause intense pain whenever the affected area is moved. The inflammation of the tissues around the joint also causes the skin to be swollen, tender and sore if it is even slightly touched. For example, a blanket or even the lightest sheet draping over the affected area could cause extreme pain.
Gout usually attacks the big toe (approximately 75 percent of first attacks); however, it also can affect other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers, and spine. In some cases, the condition may appear in the joints of small toes that have become immobile due to impact injury earlier in life, causing poor blood circulation that leads to gout.

Hernia Repair animation


It is generally advisable to repair hernias in a timely fashion, in order to prevent complications such as organ dysfunction, gangrene, and multiple organ dysfunction syndrome. Most abdominal hernias can be surgically repaired, and recovery rarely requires long-term changes in lifestyle. Uncomplicated hernias are principally repaired by pushing back, or "reducing", the herniated tissue, and then mending the weakness in muscle tissue (an operation called herniorrhaphy). If complications have occurred, the surgeon will check the viability of the herniated organ, and resect it if necessary. Modern muscle reinforcement techniques involve synthetic materials (a mesh prosthesis) that avoid over-stretching of already weakened tissue (as in older, but still useful methods). The mesh is placed over the defect, and sometimes staples are used to keep the mesh in place. Evidence suggests that this method has the lowest percentage of recurrences and the fastest recovery period. Increasingly, some repairs are performed through laparoscopes.

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Many patients are managed through day surgery centers, and are able to return to work within a week or two, while heavy activities are prohibited for a longer period. Patients who have their hernias repaired with mesh often recover in a number of days. Surgical complications have been estimated to be up to 10%, but most of them can be easily addressed. They include surgical site infections, nerve and blood vessel injuries, injury to nearby organs, and hernia recurrence.

Generally, the use of external devices to maintain reduction of the hernia without repairing the underlying defect (such as hernia trusses, trunks, belts, etc.), is not advised. Exceptions are uncomplicated incisional hernias that arise shortly after the operation (should only be operated after a few months), or inoperable patients.

It is essential that the hernia not be further irritated by carrying out strenuous labour.

What is Cell Cycle Proteins

Sequential activation of members of the cyclin-dependent protein kinase (CDK) family promotes the correct timing and ordering of events required for cell growth and cell division . In addition to driving progress through the cell cycle, CDKs are also the downstream targets of checkpoint pathways. These checkpoints act to ensure that critical cell cycle events have been successfully completed before the cell progresses into the next cell cycle stage. They are composed of a surveillance system that detects when a particular cell cycle event has not been correctly executed and a signal transduction pathway whose ultimate target can be a CDK.
 Monomeric CDKs are inactive and require both association with a positive regulatory subunit, called a cyclin, and phosphorylation on a conserved threonine residue that lies within the activation loop for full activity. Both the CDK and cyclin families have multiple members, but only CDKs 1, 2, 4 and 6, when bound to their cognate cyclins, appear to have major roles in controlling cell cycle progression. These CDK/cyclin complexes are then additionally controlled by mechanisms that include inhibitory phosphorylation, protein association, subcellular localisation and targeted destruction of regulatory proteins.

Major Histocompatibility Complex

Necrosis VS Apoptosis

Extrinsic and Intrinsic pathway for Apoptosis

Overview of the Extrinsic and Intrinsic pathway for Apoptosis

AVM Embolization

Arteriovenous malformations are abnormal clusters of blood vessels which can be seen in any part of the human body. They are congenital in nature. In he brain ,AVM's may have no symptoms at all and the abnormality may be picked during a brain scan for another reason. However, one the commonest presentations is with a bleed in the brain resulting in paralysis or unconsciousness . Another form of presentation can be seizures . Its also known that AVM,s can at time's result in frequent head aches termed "vascular headaches". When detected, AVMs are ideally treated to prevent bleeding in future.




Gleevec

Oxyhemoglobin dissociation curve

The oxygen–haemoglobin dissociation curve (or oxygen–hemoglobin dissociation curve) plots the proportion of haemoglobin in its saturated form on the vertical axis against the prevailing oxygen tension on the horizontal axis. The oxyhaemoglobin dissociation curve is an important tool for understanding how our blood carries and releases oxygen. Specifically, the oxyhaemoglobin dissociation curve relates oxygen saturation (SO2) and partial pressure of oxygen in the blood (PO2), and is determined by what is called "haemoglobin's affinity for oxygen"; that is, how readily haemoglobin acquires and releases oxygen molecules into the fluid that surrounds it.




Bilirubin Metabolism

Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal heme catabolism. Heme is formed from hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile, and its levels are elevated in certain diseases. It is responsible for the yellow color of bruises and the yellow discoloration in jaundice.
Function:
Bilirubin is created by the activity of biliverdin reductase on biliverdin. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.




Metabolism

Erythrocytes (red blood cells) generated in the bone marrow are disposed of in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme, as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the macrophages of the spleen. This unconjugated bilirubin is not soluble in water. It is then bound to albumin and sent to the liver.

In the liver it is conjugated with glucuronic acid, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic bacteria to urobilinogen, which is further metabolized to stercobilinogen, and finally oxidised to stercobilin. This stercobilin gives feces its brown color. Some of the urobilinogen is reabsorbed and excreted in the urine along with an oxidized form, urobilin.

Normally, a tiny amount of bilirubin is excreted in the urine, accounting for the light yellow color. If the liver’s function is impaired or when biliary drainage is blocked, some of the conjugated bilirubin leaks out of the hepatocytes and appears in the urine, turning it dark amber. The presence of this conjugated bilirubin in the urine can be clinically analyzed, and is reported as an increase in urine bilirubin. However, in disorders involving hemolytic anemia, an increased number of red blood cells are broken down, causing an increase in the amount of unconjugated bilirubin in the blood. As stated above, the unconjugated bilirubin is not water soluble, and thus one will not see an increase in bilirubin in the urine. Because there is no problem with the liver or bile systems, this excess unconjugated bilirubin will go through all of the normal processing mechanisms that occur (e.g., conjugation, excretion in bile, metabolism to urobilinogen, reabsorption) and will show up as an increase in urine urobilinogen. This difference between increased urine bilirubin and increased urine urobilinogen helps to distinguish between various disorders in those systems.

TCOYD Diabetes-Pregnancy II

Steven Edelman, MD and perinatal specialist Thomas Moore, MD, discuss gestational diabetes including the causes, therapies, and recommendations for keeping mother and baby healthy throughout the pregnancy and delivery.

Mechanism of Capsaicin Pain Relief

The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1). First cloned in 1997, VR1 is an ion channel-type receptor. VR1, which can also be stimulated with heat and physical abrasion, permits cations to pass through the cell membrane and into the cell when activated. The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the VR1 receptor, the capsaicin molecule produces the same sensation that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin is described as a burning sensation.
The VR1 ion channel has subsequently been shown to be a member of the superfamily of TRP ion channels, and as such is now referred to as TRPV1. There are a number of different TRP ion channels that have been shown to be sensitive to different ranges of temperature and probably are responsible for our range of temperature sensation. Thus, capsaicin does not actually cause a chemical burn, or indeed any direct tissue damage at all, when chili peppers are the source of exposure. The inflammation resulting from exposure to Capsaicin is believed to be the result of the body's reaction to nerve excitement. For example, the mode of action of capsaicin in inducing bronchoconstriction is thought to involve stimulation of C fibres culminating in the release of neuropeptides. Basically, the body inflames tissues as if it has undergone a burn or abrasion and the resulting inflammation can cause tissue damage in cases of extreme exposure, as is the case for many substances that trick the body into inflaming itself.

Telomere Replication

The ends of linear chromosomes pose unique problems during DNA replication. This video shows how molecular mechanisms solve these problems.

T cell response to MHC II

Tumor Destruction

A Tumor or tumour (via Old French tumour from Latin tumor "swelling")originally meant an abnormal swelling of the flesh. In contemporary English, tumor has evolved to become synonymous with neoplasia , all other forms being called swelling . This tendency has also become common in medical literature. The noun tumefaction, derived from the adjective tumefied, is the current medical term for non-neoplastic tumors .


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Tumors and/or swellings can be caused by:
Other forms of swelling are part of the normal functions of the body and may or may not be included as causes of tumor. Examples include enlargement of the uterus in pregnancy and erection of the penis.


  • Neoplasia, an abnormal proliferation of tissues. Most (not all) neoplasms cause a tumor. Neoplasms (or tumors) may be benign or malignant (cancer).
  • Non-neoplastic causes :
  1. Inflammation, by far the most common cause; tumor is one of the classic signs of inflammation. The lump following a blow on the head is a typical example. Infection is another common cause of inflammation.
  2. Edema, the accumulation of an excessive amount of fluid in the tissues, either with or without inflammation.
  3. Malformation, a congenital anomaly in the architecture of a tissue. A typical example is an epidermal nevus.
  4. Cyst, the accumulation of fluid in a closed structure. Breast cysts are a typical example.
  5. Hemorrhage in a closed structure.

Rheumatoid Arthritis Animation

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder that causes the immune system to attack the joints, causing inflammation (arthritis), and some organs, such as the lungs and skin. It can be a disabling and painful condition, which can lead to substantial loss of functioning mobility due to pain and joint destruction. It is diagnosed with blood tests (especially a test called rheumatoid factor) and X-rays. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in the diseases of joints and connective tissues.

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Various treatments are available. Non-pharmacological treatment includes physical therapy and occupational therapy. Analgesia (painkillers) and anti-inflammatory drugs, as well as steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are often required to reverse the disease process and prevent long-term damage. Classic DMARDs are methotrexate and sulfasalazine, but also the newer group of biologics which includes highly-effective agents such as infliximab (Remicade), etanercept (Embrel), adalimumab (Humira), abatacept (Orencia) and rituximab (Rituxan/Mabthera).


The name is based on the term "rheumatic fever", an illness which includes joint pain and is derived from the Greek word rheumatos ("flowing"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of rheumatoid arthritis was made in 1800 by Dr Augustin Jacob Landré-Beauvais (1772-1840) of Paris.

Signs and symptoms

While rheumatoid arthritis primarily affects joints, problems involving all other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations occur in about 15% of individuals with rheumatoid arthritis. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it - for example, lung fibrosis from methotrexate, or osteoporosis from corticosteroids.

Joints
The arthritis of rheumatoid arthritis is due to synovitis, which is inflammation of the synovial membrane that covers the joint. Joints become red, swollen, tender and warm, and stiffness prevents their use. By definition, RA affects multiple joints (it is a polyarthritis). Most commonly, small joints of the hands, feet and cervical spine are affected, but larger joints like the shoulder and knee can also be involved, differing per individual. Eventually, synovitis leads to erosion of the joint surface, causing deformity and loss of function.

Inflammation in the joints manifests itself as a soft, "doughy" swelling, causing pain and tenderness to palpation and movement, a sensation of localised warmth, and restricted movement. Increased stiffness upon waking is often a prominent feature and may last for more than an hour. These signs help distinguish rheumatoid from non-inflammatory diseases of the joints such as osteoarthritis (sometimes referred to as the "wear-and-tear" of the joints). In RA, the joints are usually affected in a fairly symmetrical fashion although the initial presentation may be asymmetrical.

As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes. Common deformities in rheumatoid arthritis are the Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint), swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-Thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, and hyperextension at the IP joint.

Skin

The rheumatoid nodule is the cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion(a part of an organ or tissue which has been damaged) is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. Rarely, they can occur in internal organs.

Several forms of vasculitis are also cutaneous manifestations associated with rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.)

Other, rather rare, skin associated symtoms include:

* pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis.
* Sweet's syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders
* drug reactions
* erythema nodosum
* lobular panniculitis
* atrophy of digital skin
* palmar erythema
* diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).

DMT biosynthesis

Dimethyltryptamine (DMT), also known as N,N-dimethyltryptamine, is a naturally-occurring tryptamine and potent psychedelic drug,found not only in many plants, but also in trace amounts in the human body where its natural function is undetermined. Structurally, it is analogous to the neurotransmitter serotonin and other psychedelic tryptamines such as 5-MeO-DMT and 4-HO-DMT. DMT is created in small amounts by the human body during normal metabolism by the enzyme tryptamine-N-methyltransferase. Many cultures, indigenous and modern, ingest DMT as a psychedelic in extracted or synthesized forms. Pure DMT at room temperature is a clear or white to yellowish-red crystalline solid. A laboratory synthesis of DMT was first reported in 1931, and it was later found in many plants





Dimethyltryptamine. (2009, June 16). In Wikipedia, The Free Encyclopedia. Retrieved 03:23, June 16, 2009, from http://en.wikipedia.org/w/index.php?title=Dimethyltryptamine&oldid=296681896

Tryptophan Operon


Trp operon is an operon in bacteria which promotes the production of tryptophan when tryptophan isn't present in the environment. Discovered in 1953 by Jacques Monod and colleagues, the trp operon in E. coli was the first repressible operon to be discovered. While the lac operon can be activated by a chemical (allolactose), the tryptophan (Trp) operon is inhibited by a chemical (tryptophan). This operon contains five structural genes: trp E, trp D, trp C, trp B, and trp A, which encodes tryptophan synthetase. It also contains a promoter which binds to RNA polymerase and an operator which blocks transcription when bound to the protein synthesized by the repressor gene (trp R) that binds to the operator. In the lac operon, lactose binds to the repressor protein and prevents it from repressing gene transcription, while in the trp operon, tryptophan binds to the repressor protein and enables it to repress gene transcription. Also unlike the lac operon, the trp operon contains a leader peptide and an attenuator sequence which allows for graded regulation.

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It is an example of negative regulation of gene expression. Within the operon's regulatory sequence, the operator is blocked by the repressor protein in the presence of tryptophan (thereby preventing transcription) and is liberated in tryptophan's absence (thereby allowing transcription). The process of attenuation complements this regulatory action. Repression The repressor for the trp operon is produced upstream by the trpR gene, which is continually expressed. It creates monomers, which associate into tetramers. When tryptophan is present, it binds to the tryptophan repressor tetramers, and causes a change in conformation, which allows the repressor to bind the operator, which prevents RNA polymerase from binding or transcribing the operon, so tryptophan is not produced. When tryptophan is not present, the repressor cannot bind the operator, so transcription can occur. This is therefore a negative feedback mechanism.

Attenuation Because repression of this operon is still "leaky," another system of controlling expression is also needed: Attenuation. At the beginning of the transcribed genes of the trp operon is a leader sequence, which codes for a very short polypeptide. Near the end of this sequence, two tryptophans are coded for next to each other. Because tryptophan is a fairly uncommon amino acid, this is highly unusual. Since in prokaryotes the ribosomes begin translating the mRNA as soon as the RNA polymerase has moved farther down the DNA sequence, upstream translation occurs simultaneously with transcription of downstream genes. So, as soon as the polymerase has created the mRNA for the leader sequence, it is being translated. When the ribosome reaches the double-trp codons, if enough trp is present, the ribosome will not be delayed, and will continue translating until it reaches the stop codon and falls off the leader transcript. A hairpin will then form in the mRNA transcript (remember, still attached to RNA polymerase on other end) between regions 1-2, and 3-4, which destabilizes the RNA polymerase and halts transcription of the rest of the operon, thus preventing production of trp. On the other hand, if there is little or no trp available, the ribosome will be delayed or stopped on the double-trp, and a hairpin will form between regions 2-3 of the mRNA instead. This does not destabilize the polymerase, so transcription and translation occur. Similar mechanism regulates the synthesis of histidine, phenylalanine and threonine.

Endoscopy of Large Intestine


Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an instrument called an endoscope. Endoscopy can also refer to using a borescope in technical situations where direct line-of-sight observation is not feasible.





Endoscopy is a minimally invasive diagnostic medical procedure that is used to assess the interior surfaces of an organ by inserting a tube into the body. The instrument may have a rigid or flexible tube and not only provide an image for visual inspection and photography, but also enable taking biopsies and retrieval of foreign objects. Endoscopy is the vehicle for minimally invasive surgery.



Many endoscopic procedures are considered to be relatively painless and, at worst, associated with mild discomfort; for example, in esophagogastroduodenoscopy, most patients tolerate the procedure with only topical anaesthesia of the oropharynx using lignocaine spray. Complications are not common (only 5% of all operations)but can include perforation of the organ under inspection with the endoscope or biopsy instrument. If that occurs open surgery may be required to repair the injury.

Deciphering the Human Genome

Herceptin: Mechanism of action


Herceptin is a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor. Trastuzumab's principal use is as an anti-cancer therapy in breast cancer in patients whose tumors over express (produce more than the usual amount of) this receptor. Trastuzumab is administered either once a week or once every three weeks intravenously for 30 to 90 minutes.

Amplification of HER2/neu (ErbB2) occurs in 25-30% of early-stage breast cancers.[1] It encodes the extracellular domain of her2. Although the signaling pathways induced by the HER2/neu receptor are incompletely characterized, it is thought that activation of the PI3K/Akt pathway is important. This pathway is normally associated with mitogenic signaling involving the MAPK pathway. However in cancer the growth promoting signals from HER2/neu are constitutively transmitted — promoting invasion, survival and angiogenesis of cells.[2] Furthermore overexpression can also confer therapeutic resistance to cancer therapies. The prime mechanism that causes increase in proliferation speed is due to induction of p27Kip1, an inhibitor of cdk2 and of cell proliferation, to remain in the cytoplasm instead of translocation in to the nucleus.[3] This is caused by phosphorylation by Akt.

Herceptin is a humanized monoclonal antibody which binds to the extracellular segment of the HER2/neu receptor. Cells treated with trastuzumab undergo arrest during the G1 phase of the cell cycle so there is reduced proliferation. It has been suggested that trastuzumab induces some of its effect by downregulation of HER2/neu leading to disruption of receptor dimerization and signaling through the downstream PI3K cascade. P27Kip1 is then not phosphorylated and is able to enter the nucleus and inhibit cdk2 activity, causing cell cycle arrest.[3] Also, trastuzumab suppresses angiogenesis by both induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.[4] There may be other undiscovered mechanisms by which trastuzumab induces regression in cancer.

T cell lymphocyte


T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and NK cells by the presence of a special receptor on their cell surface called the T cell receptor (TCR). The abbreviation T, in T cell, stands for thymus, since it is the principal organ in the T cell's development.


Several different subsets of T cells have been described, each with a distinct function.


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  • Helper T cells (TH cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Depending on the cytokine signals received, these cells differentiate into TH1, TH2, TH17, or one of other subsets, which secrete different cytokines.
  • Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells, since they express the CD8 glycoprotein at their surface. Through interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.
  • Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.
  • Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
  • Natural Killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules).
  • γδ T cells represent a small subset of T cells that possess a distinct TCR on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, HMB-PP, an isopentenyl pyrophosphate precursor.

T cell Activation


Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility complex peptide and B7 family members on the APC, respectively. Both are required for production of an effective immune response; in the absence of CD28 co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve many proteins.

The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a dendritic cell in the case of naïve responses, although B cells and macrophages can be important APCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open.

The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation.

The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, Trim, LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins.

Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries di-acyl glycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the release of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long term proliferation of activated T cells.

Pathogen Recognition Receptors

Cells in the immune system like Macrophages and dendritic cells are the first line of defense in recognizing various kinds pathogens.These cells are developed several kind of receptors for recognizing different types of pathogen Associated Molecular patterns known as PAMPs.
There are different classes of these proteins, they recognize different types of PAMPs, Toll-like receptor (TLR) is composed of multiple leucine-rich repeats that are useful for recognizing various PAMPs.Each members of TLR family recognize different kinds of PAMPs,For example TLR5 recognizes flagellin,which is highly conserver constituent of the bacterial flagellum.





Bacterial genomes contain methylated CPG oligonucleotide motifs, which are recognized by TLR9, once the genome is degraded in the lysosome.
TLR6 and TLR2 are dimers,that recognize diacyllipopeptide.
TLR1 and TLR2 are dimers that recognize triacyllipopetide and TLR4 recognize lipopolysaccharide (LPS) a component of Gram Negative bacteria.
Like TLR9 TLR3 and TLR7 are located endocylic vesciles and recognize double stranded RNA and single stranded RNA respectively.
When any TLRs activated, it sends the signal to nucleus by activating transcription factors.
Some pathogens such as viruses exists and replicate in cytosol.there are at least two classes receptors that an detect pathogens in cytosol and signal their presence to the immune system.One class of such receptors are members of nuclear oligomerization domain family or NOD proteins.
For example NOD 2 protein, which is located in the cytosol, can detect bacterioproteoglycans of intracellular bacteria.When NOD2 protein recognizes its ligands the muramyl dipeptide, it sends the signal to nucleus to activate transcription.
Finally there is a class intracellular receptor protein that can contain a RNA helicase domain and two caspase recruitment domains, one member of this family RIG-I recognizes double stranded RNAs that are component of life cycle of many RNA virus,
This class of proteins also sends the signal to nucleus, but unlike TLRs it activates the production type 1 interferons. In all the toll like receptors, NOR proteins and RNA helicase domain family provide the innate immune system with the ability to detect both extra cellular and intracellular pathogens and to activate immune response

What is Hemolysis

Hemolysis is the breakdown of red blood cells. The ability of bacterial colonies to induce hemolysis when grown on blood agar is used to classify certain microorganisms. This is a particularly useful in classifying streptococcal species. A substance that causes hemolysis is a hemolysin.
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Types of hemolysis Alpha
When Alpha hemolysis (α-hemolysis) is present the agar under the colonies is dark and greenish. Streptococcus pneumoniae and a group of oral streptococci (Streptococcus viridans or viridans streptococci) display alpha hemolysis. This is sometimes called green hemolysis because of the color change in the agar. Other synonymous terms are incomplete hemolysis and partial hemolysis. Alpha hemolysis is generally caused by peroxides produced by the bacterium.
The bacterium Staphylococcus aureus, a common cause of infection in humans, secretes a toxin known as alpha-hemolysin that kills human cells by forming holes in their membranes, through which chemicals essential to survival leak out. The movie illustrates the structure of the hole, which is created when identical proteins released by the bacterium (in pink, yellow, gold, red, grey, green, and white) assemble in groups of seven in the cell's membrane (in cyan).
Beta
Beta hemolysis (β-hemolysis), sometimes called complete hemolysis, is a complete lysis of red cells in the media around and under the colonies: the area appears lightened and transparent. Streptococcus pyogenes, or Group A beta-hemolytic Strep (GAS), displays beta hemolysis.
Some weakly beta-hemolytic species cause intense beta hemolysis when grown together with a strain of Staphylococcus. This is called the CAMP test1. Streptococcus agalactiae displays this property. Clostridium perfringens can be identified presumptively with this test.


If an organism does not induce hemolysis, it is said to display gamma hemolysis (γ-hemolysis): the agar under and around the colony is unchanged (this is also called non-hemolytic). Enterococcus faecalis (formerly called Group D Strep) displays gamma hemolysis.

Rh Factor

Individuals either have, or do not have, the Rhesus factor (or Rh D antigen) on the surface of their red blood cells. This is usually indicated by 'RhD positive' (does have the RhD antigen) or 'RhD negative' (does not have the antigen) suffix to the ABO blood type. Unlike the ABO antigens, the only ways antibodies are developed against the Rh factor are through placental sensitization or translation. That is, if a person who is RhD-negative has never been exposed to the RhD antigen, they do not possess the RhD antibody. The 'RhD-' suffix is often shortened to 'D pos'/'D neg', 'RhD pos'/RhD neg', or +/-. The latter is generally not preferred in research or medical situations, because it can be altered or obscured accidentally.


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There may be prenatal danger to the fetus when a pregnant woman is RhD-negative and the biological father is RhD-positive. But, as discussed below, the situation is considerably more complex than that.




Rh factor, protein substance present in the red blood cells of most people, capable of inducing intense antigenic reactions. The Rh, or rhesus, factor was discovered in 1940 by K. Landsteiner and A. S. Wiener, when they observed that an injection of blood from a rhesus monkey into rabbits caused an antigenic reaction in the serum component of rabbit blood (see immunity). When blood from humans was tested with the rabbit serum, the red blood cells of 85% of the humans tested agglutinated (clumped together). The red blood cells of the 85% (later found to be 85% of the white population and a larger percentage of blacks and Asians) contained the same factor present in rhesus monkey blood; such blood was typed Rh positive. The blood of the remaining 15% lacked the factor and was typed Rh negative. Under ordinary circumstances, the presence or lack of the Rh factor has no bearing on life or health. It is only when the two blood types are mingled in an Rh-negative individual that the difficulty arises,


Since the Rh factor acts as an antigen in Rh-negative persons, causing the production of antibodies. Besides the Rh factor, human red blood cells contain a large number of additional antigenic substances that have been classified into many blood group systems (see blood groups); however, the Rh system is the only one, aside from the ABO system, that is of major importance in blood transfusions. If Rh-positive blood is transfused into an Rh-negative person, the latter will gradually develop antibodies called anti-Rh agglutinins, that attach to the Rh-positive red blood cells, causing them to agglutinate. Destruction of the cells (hemolysis) eventually results. If the Rh-negative recipient is given additional transfusions of Rh-positive blood, the concentration of anti-Rh agglutinins may become high enough to cause a serious or fatal reaction. The same type of immune reaction occurs in the blood of an Rh-negative mother who is carrying an Rh-positive fetus. (The probability of this situation occurring is high if the father is Rh positive.) Some of the infant's blood may enter the maternal circulation, causing the formation of agglutinins against the fetal red blood cells. The first baby is usually not harmed. But, if the mother's agglutinins pass into the circulation of subsequent fetuses, they may destroy the fetal red blood cells, causing the severe hemolytic disease of newborns known as erythroblastosis fetalis

HIV Drug groups - Protease inhibitors


Protease inhibitors (PIs) are a class of medications used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new virons.
Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:
HIV/AIDS: antiretroviral protease inhibitors such assaquinavir, ritonavir, indinavir, nelfinavir etc.

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Saquinavir
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Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:
a hard-gel capsule formulation of the mesylate, with trade name Invirase®, which requires combination with ritonavir to increase the saquinavir bioavailability; a soft-gel capsule formulation of saquinavir, with trade name Fortovase®. Both formulations are generally used as a component of highly active antiretroviral therapy (HAART). Ritonavir
Ritonavir, with trade name Norvir® (Abbott Laboratories), is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.
Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.

Indinavir
Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy (HAART) to treat HIV infection and AIDS.
Nelfinavir
Nelfinavir (Viracept®) is an antiretroviral drug used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is generally used in combination with other antiretroviral drugs. Nelfinavir is presented as the mesilate (mesylate) ester prodrug.
Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. Nelfinavir mesylate contains the Castor oil derivative Cremophor EL

Protein Folding

Protein folding is the physical process by which a polypeptide folds into its characteristic three-dimensional structure.

Each protein begins as a polypeptide, translated from a sequence of mRNA as a linear chain of amino acids. This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). However each amino acid in the chain can be thought of having certain 'gross' chemical features. These may be hydrophobic, hydrophilic, or electrically charged, for example. These interact with each other and their surroundings in the cell to produce a well-defined, three dimensional shape, the folded protein (the right hand side of the figure), known as the native state. The resulting three-dimensional structure is determined by the sequence of the amino acids. The mechanism of protein folding is not completely understood.


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Experimentally determining the three dimensional structure of a protein is often very difficult and expensive. However the sequence of that protein is often known. Therefore scientists have tried to use different biophysical techniques to manually fold a protein. That is, to predict the structure of the complete protein from the sequence of the protein.

For many proteins the correct three dimensional structure is essential to function. Failure to fold into the intended shape usually produces inactive proteins with different properties (details found under prion). Several neurodegenerative and other diseases are believed to result from the accumulation of misfolded (incorrectly folded) proteins.
A simulation of protein folding in the HP lattice model from a random state to ground state with maximum number of HH contacts. The red balls are Hydrophobic amino acids.
The relationship between folding and amino acid sequence

The amino-acid sequence (or primary structure) of a protein predisposes it towards its native conformation or conformations. It will fold spontaneously during or after synthesis. While these macromolecules may be regarded as "folding themselves", the mechanism depends equally on the characteristics of the cytosol, including the nature of the primary solvent (water or lipid), the concentration of salts, the temperature, and molecular chaperones.


Most folded proteins have a hydrophobic core in which side chain packing stabilizes the folded state, and charged or polar side chains on the solvent-exposed surface where they interact with surrounding water molecules. It is generally accepted that minimizing the number of hydrophobic sidechains exposed to water is the principal driving force behind the folding process,although a recent theory has been proposed which reassesses the contributions made by hydrogen bonding.

The process of folding in vivo often begins co-translationally, so that the N-terminus of the protein begins to fold while the C-terminal portion of the protein is still being synthesized by the ribosome. Specialized proteins called chaperones assist in the folding of other proteins.A well studied example is the bacterial GroEL system, which assists in the folding of globular proteins. In eukaryotic organisms chaperones are known as heat shock proteins. Although most globular proteins are able to assume their native state unassisted, chaperone-assisted folding is often necessary in the crowded intracellular environment to prevent aggregation; chaperones are also used to prevent misfolding and aggregation which may occur as a consequence of exposure to heat or other changes in the cellular environment.

For the most part, scientists have been able to study many identical molecules folding together en masse. At the coarsest level, it appears that in transitioning to the native state, a given amino acid sequence takes on roughly the same route and proceeds through roughly the same intermediates and transition states. Often folding involves first the establishment of regular secondary and supersecondary structures, particularly alpha helices and beta sheets, and afterwards tertiary structure. Formation of quaternary structure usually involves the "assembly" or "coassembly" of subunits that have already folded. The regular alpha helix and beta sheet structures fold rapidly because they are stabilized by intramolecular hydrogen bonds, as was first characterized by Linus Pauling. Protein folding may involve covalent bonding in the form of disulfide bridges formed between two cysteine residues or the formation of metal clusters. Shortly before settling into their more energetically favourable native conformation, molecules may pass through an intermediate "molten globule" state.

The essential fact of folding, however, remains that the amino acid sequence of each protein contains the information that specifies both the native structure and the pathway to attain that state. This is not to say that identical amino acid sequences always fold similarly. Conformations differ based on environmental factors as well; similar proteins fold differently based on where they are found. Folding is a spontaneous process independent of energy inputs from nucleoside triphosphates. The passage of the folded state is mainly guided by hydrophobic interactions, formation of intramolecular hydrogen bonds, and van der Waals forces, and it is opposed by conformational entropy, which must be overcome by extrinsic factors such as chaperones.


Disruption of the native state
In certain solutions and under some conditions proteins will not fold into their biochemically functional forms. Temperatures above (and sometimes those below) the range that cells tend to live in will cause proteins to unfold or "denature" (this is why boiling makes an egg white turn opaque). High concentrations of solutes, extremes of pH, mechanical forces, and the presence of chemical denaturants can do the same. A fully denatured protein lacks both tertiary and secondary structure, and exists as a so-called random coil. Under certain conditions some proteins can refold; however, in many cases denaturation is irreversible. Cells sometimes protect their proteins against the denaturing influence of heat with enzymes known as chaperones or heat shock proteins, which assist other proteins both in folding and in remaining folded. Some proteins never fold in cells at all except with the assistance of chaperone molecules, which either isolate individual proteins so that their folding is not interrupted by interactions with other proteins or help to unfold misfolded proteins, giving them a second chance to refold properly. This function is crucial to prevent the risk of precipitation into insoluble amorphous aggregates.

Incorrect protein folding and neurodegenerative disease
Misfolded proteins are responsible for prion-related illnesses such as Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), amyloid-related illnesses such as Alzheimer's Disease, and a number of other forms of proteopathy such as cystic fibrosis. These diseases are associated with the multimerization of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions; it is not clear whether the plaques are the cause or merely a symptom of illness.

Kinetics and the Levinthal Paradox
The entire duration of the folding process varies dramatically depending on the protein of interest. The slowest folding proteins require many minutes or hours to fold, primarily due to proline isomerizations or wrong disulfide bond formations, and must pass through a number of intermediate states, like checkpoints, before the process is complete. On the other hand, very small single-domain proteins with lengths of up to a hundred amino acids typically fold in a single step. Time scales of milliseconds are the norm and the very fastest known protein folding reactions are complete within a few microseconds.

The Levinthal paradox observes that if a protein were to fold by sequentially sampling all possible conformations, it would take an astronomical amount of time to do so, even if the conformations were sampled at a rapid rate (on the nanosecond or picosecond scale). Based upon the observation that proteins fold much faster than this, Levinthal then proposed that a random conformational search does not occur in folding, and the protein must, therefore, fold by a directed process.

Techniques for studying protein folding
Modern studies of folding with high time resolution

The study of protein folding has been greatly advanced in recent years by the development of fast, time-resolved techniques. These are experimental methods for rapidly triggering the folding of a sample of unfolded protein, and then observing the resulting dynamics. Fast techniques in widespread use include ultrafast mixing of solutions, photochemical methods, and laser temperature jump spectroscopy. Among the many scientists who have contributed to the development of these techniques are Heinrich Roder, Harry Gray, Martin Gruebele, Brian Dyer, William Eaton, Sheena Radford, Chris Dobson, Sir Alan R. Fersht and Bengt Nölting.

Energy landscape theory of protein folding
The protein folding phenomenon was largely an experimental endeavor until the formulation of energy landscape theory by Joseph Bryngelson and Peter Wolynes in the late 1980s and early 1990s. This approach introduced the principle of minimal frustration, which asserts that evolution has selected the amino acid sequences of natural proteins so that interactions between side chains largely favor the molecule's acquisition of the folded state. Interactions that do not favor folding are selected against, although some residual frustration is expected to exist. A consequence of these evolutionarily selected sequences is that proteins are generally thought to have globally "funneled energy landscapes" (coined by José Onuchic) that are largely directed towards the native state. This "folding funnel" landscape allows the protein to fold to the native state through any of a large number of pathways and intermediates, rather than being restricted to a single mechanism. The theory is supported by both computational simulations of model proteins and numerous experimental studies, and it has been used to improve methods for protein structure prediction and design.

Computational prediction of protein tertiary structure
De novo or ab initio techniques for computational protein structure prediction is related to, but strictly distinct from, studies involving protein folding. Molecular Dynamics (MD) is an important tool for studying protein folding and dynamics in silico. Because of computational cost, ab initio MD folding simulations with explicit water are limited to peptides and very small proteins. MD simulations of larger proteins remain restricted to dynamics of the experimental structure or its high-temperature unfolding. In order to simulate long time folding processes (beyond about 1 microsecond), like folding of small-size proteins (about 50 residues) or larger, some approximations or simplifications in protein models need to be introduced. An approach using reduced protein representation (pseudo-atoms representing groups of atoms are defined) and statistical potential is not only useful in protein structure prediction, but is also capable of reproducing the folding pathways.

Because of the many possible ways of folding, there can be many possible structures. A peptide consisting of just five amino acids can fold into over 100 billion possible structures.

Techniques for determination of protein structure

The determination of the folded structure of a protein is a lengthy and complicated process, involving methods like X-ray crystallography and NMR. One of the major areas of interest is the prediction of native structure from amino-acid sequences alone using bioinformatics and computational simulation methods.

There are distibuted computing projects which use idle CPU time of personal computers to solve problems such as protein folding or prediction of protein structure. People can run these programs on their computer or PlayStation 3 to support them. See links below (for example Folding@Home) to get information about how to participate in these projects.