PLASMA PROTEIN proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum. Serum albumin accounts for 55% of blood proteins,[1] is a major contributor to maintaining the oncotic pressure of plasma and assists, as a carrier, in the transport of lipids and steroid hormones. Globulins make up 38% of blood proteins and transport ions, hormones, and lipids assisting in immune function. Fibrinogen comprises 7% of blood proteins; conversion of fibrinogen to insoluble fibrin is essential for blood clotting. The remainder of the plasma proteins (1%) are regulatory proteins, such as enzymes, proenzymes, and hormones. All blood proteins are synthesized in liver except for the gamma globulins.[1]

Families of blood proteins[edit]

Normal Blood protein % Function level

3.5-5.0 create and maintain osmotic pressure; transport

Albumins 55% g/dl insoluble molecules

2.0-2.5

Globulins 38% participate in immune system g/dl

0.2-0.45

Fibrinogen 7% Blood coagulation g/dl

Regulatory <1% Regulation of gene expression proteins

Clotting factors <1% Conversion of fibrinogen into fibrin

Examples of specific blood proteins:

• Prealbumin (transthyretin) • Alpha 1 antitrypsin (neutralizes trypsin that has leaked from the digestive system) • Alpha-1-acid glycoprotein • Alpha-1-fetoprotein • alpha2-macroglobulin • Gamma globulins • Beta-2 microglobulin • Haptoglobin • Ceruloplasmin • Complement component 3 • Complement component 4 • C-reactive protein (CRP) • Lipoproteins (chylomicrons, VLDL, LDL, HDL) • Transferrin • Prothrombin • MBL or MBP

Clinical significance Separating serum proteins by electrophoresis is a valuable diagnostic tool, as well as a way to monitor clinical progress. Current research regarding blood plasma proteins is centered on performing proteomics analyses of serum/plasma in the search for biomarkers. These efforts started with two-dimensional gel electrophoresis[2] efforts in the 1970s, and in more recent times this research has been performed using LC-tandem MS[3][4][5] based proteomics. The normal laboratory value of serum total protein is around 7 g/dL.

HAEMOPOISIS Haemopoiesis describes the formation of blood cells. During embryonic development, the haemopoietic system is sequentially derived from the aorta–gonad–mesonephros part of the mesoderm, the haemangioblast, the haemogenic endothelium and subsequently the haemopoietic progenitors. The liver is important for fetal haemopoiesis. Haemopoiesis in children and adults occurs mainly in bone marrow, with some contribution from other sites. The bone marrow microenvironmental niche and other factors are crucial for regulating haemopoiesis in the face of changing demand. Haemopoietic stem cells are multipotent progenitors from which the cells of the blood and immune systems are ultimately derived. They are capable of limited self-renewal as well as proliferation and differentiation into lineage- restricted cells. Haemopoietic stem cells give rise to lymphoid and myeloid precursors. Differentiation of myeloid precursors forms granulocytes, thrombocytes and erythrocytes.

1. Red blood cells (erythrocytes): These transport oxygen and hemoglobin throughout the body.

2. White blood cells (leukocytes): These support the immune system. There are several different types of white blood cells:

• Lymphocytes: Including T cells and B cells, which help fight some viruses and tumors. • Neutrophils: These helps fight bacterial and fungal infections. • Eosinophils: These play a role in the inflammatory response, and help fight some parasites. • Basophils: These release the histamines necessary for the inflammatory response. • Macrophages: These engulf and digest debris, including bacteria.

3. Platelets (thrombocytes): These help the blood to clot.

Current research endorses a theory of haematopoiesis called the monophyletic theory. This theory says that one type of stem cell produces all types of blood cells.

Hematopoiesis occurs in many places: Hematopoiesis in the embryo Share on PinterestHematopoiesis in the embryo provides organs with oxygen. Sometimes called primitive hematopoiesis, hematopoiesis in the embryo produces only red blood cells that can provide developing organs with oxygen. At this stage in development, the yolk sac, which nourishes the embryo until the placenta is fully developed, controls hematopoiesis.

As the embryo continues to develop, the hematopoiesis process moves to the liver, the spleen, and bone marrow, and begins producing other types of blood cells. In adults, hematopoiesis of red blood cells and platelets occurs primarily in the bone marrow. In infants and children, it may also continue in the spleen and liver. The lymph system, particularly the spleen, lymph nodes, and thymus, produces a type of white blood cell called lymphocytes. Tissue in the liver, spleen, lymph nodes and some other organs produce another type of white blood cells, called monocytes.

The process of hematopoiesis : The rate of hematopoiesis depends on the body’s needs. The body continually manufactures new blood cells to replace old ones. About 1 percent of the body’s blood cells must be replaced every day. White blood cells have the shortest life span, sometimes surviving just a few hours to a few days, while red blood cells can last up to 120 days or so. The process of hematopoiesis begins with an unspecialized stem cell. This stem cell multiplies, and some of these new cells transform into precursor cells. These are cells that are destined to become a particular type of blood cell but are not yet fully developed. However, these immature cells soon divide and mature into blood components, such as red and white blood cells, or platelets.

Each type of blood cell follows a slightly different path of hematopoiesis. All begin as stem cells called multipotent hematopoietic stem cells (HSC). From there, hematopoiesis follows two distinct pathways. Trilineage hematopoiesis refers to the production of three types of blood cells: platelets, red blood cells, and white blood cells. Each of these cells begins with the transformation of HSC into cells called common myeloid progenitors (CMP). After that, the process varies slightly. At each stage of the process, the precursor cells become more organized:

Red blood cells and platelets

• Red blood cells: CMP cells change five times before finally becoming red blood cells, also known as erythrocytes. • Platelets: CMP cells transform into three different cell types before becoming platelets.

White blood cells

There are several types of white blood cells, each following an individual path during hematopoiesis. All white blood cells initially transform from CMP cells into to myeoblasts. After that, the process is as follows:

• Before becoming a neutrophil, eosinophil, or basophil, a myeoblast goes through four further stages of development. • To become a macrophage, a myeoblast has to transform three more times.

A second pathway of hematopoiesis produces T and B cells. T cells and B cells To produce lymphocytes, MHCs transform into cells called common lymphoid progenitors, which then become lymphoblasts. Lymphoblasts differentiate into infection-fighting T cells and B cells. Some B cells differentiate into plasma cells after exposure to infection. Impact on health Share on PinterestAnemia may occur if the blood lacks hemoglobin. Some blood disorders can affect healthy blood cells in the blood, even when hematopoiesis occurs.

For example, cancers of the white blood cells such as leukemia and lymphoma can alter the number of white blood cells in the bloodstream. Tumors in hematopoietic tissue that produces blood cells, such as bone marrow can affect blood cell counts.

The aging process can increase the amount of fat present in the bone marrow. This increase in fat can make it harder for the marrow to produce blood cells. If the body needs additional blood cells due to an illness, the bone marrow is unable to stay ahead of this demand. This can cause anemia, which occurs when the blood lacks hemoglobin from red blood cells.

Hematopoiesis is a constant process that produces a massive number of cells. Estimates vary, and the precise number of cells depends on individual needs. But in a typical day, the body might produce 200 billion red blood cells, 10 million white blood cells, and 400 billion platelets.

PHYSIOLOGY OF CLOTTING Coagulation, in physiology, the process by which a blood clot is formed. The formation of a clot is often referred to as secondary hemostasis, because it forms the second stage in the process of arresting the loss of blood from a ruptured vessel. The first stage, primary hemostasis, is characterized by blood vessel constriction (vasoconstriction) and platelet aggregation at the site of vessel injury. Under abnormal circumstances, clots can also form in a vessel that has not been breached; such clots can result in the occlusion (blockage) of the vessel (see thrombosis). fibrin in blood clotting Red blood cells (erythrocytes) trapped in a mesh of fibrin threads. Fibrin, a tough, insoluble protein formed after injury to the blood vessels, is an essential component of blood clots. BSIP/age fotostock

Clotting is a sequential process that involves the interaction of numerous blood components called coagulation factors. There are 13 principal coagulation factors in all, and each of these has been assigned a Roman numeral, I to XIII. Coagulation can be initiated through the activation of two separate pathways, designated extrinsic and intrinsic. Both pathways result in the production of factor X. The activation of this factor marks the beginning of the so-called common pathway of coagulation, which results in the formation of a clot.

The blood coagulation cascade is initiated through either the extrinsic or intrinsic pathway. Both pathways result in the production of factor X, an enzyme that marks the beginning of the common pathway of coagulation, which culminates in the stabilization of a fibrin clot. Encyclopædia Britannica, Inc. The extrinsic pathway is generally the first pathway activated in the coagulation process and is stimulated in response to a protein called tissue factor, which is expressed by cells that are normally found external to blood vessels. However, when a blood vessel breaks and these cells come into contact with blood, tissue factor activates factor VII, forming factor VIIa, which triggers a cascade of reactions that result in the rapid production of factor X. In contrast, the intrinsic pathway is activated by injury that occurs within a blood vessel. This pathway begins with the activation of factor XII (Hageman factor), which occurs when blood circulates over injured internal surfaces of vessels. Components of the intrinsic pathway also may be activated by the extrinsic pathway; for example, in addition to activating factor X, factor VIIa activates factor IX, a necessary component of the intrinsic pathway. Such cross-activation serves to amplify the coagulation process.

The production of factor X results in the cleavage of prothrombin (factor II) to thrombin (factor IIa). Thrombin, in turn, catalyzes the conversion of fibrinogen (factor I)—a soluble plasma protein—into long, sticky threads of insoluble fibrin (factor Ia). The fibrin threads form a mesh that traps platelets, blood cells, and plasma. Within minutes, the fibrin meshwork begins to contract, squeezing out its fluid contents. This process, called clot retraction, is the final step in coagulation. It yields a resilient, insoluble clot that can withstand the friction of blood flow. ORIGIN AND CONDUCTION OF HEARBEAT ORIGIN, CONDUCTION & REGULATION OF HEARTBEAT

November 16, 2018 Aastha Rawal Physiology 1

Heart has intrinsic system whereby muscle contracts and relax without the involvement of brain. However, Intrinsic system can be stimulated or depressed by nerve impulses initiated by brain or hormones. The origin, conduction and regulation of heartbeat involves Sino-Atrial node (SA Node), inter-nodal pathways, atrioventricular node (AV Node), the AV bundle and

the bundle of Purkinje fibres.

SA node is a small, flattened mass of neuromuscular tissue, about 3mm wide, 15mm long and 1mm thick. It is situated near the opening of superior venacava in right atrium. Sinus nodal fibers connects directly with the atrial muscle fibers so that any action potential that begins in the sinus node transmits immediately into atrial muscle wall. The fibers of SA node has ability of self excitation and control the rate of entire heartbeat. The fibers of SA node have high concentration of Sodium ions in extracellular fluid and negative charges inside the nodal fibers. Due to high concentration and the presence of open channels, Na+ ions always tends to enter inside. The membrane permeability of K+ is gradually reduced which upsets the ionic balance of Na and K making the interior more positive. Ultimately at threshold (approx. -40mV), fast Ca++ channels open allowing entry of Calcium and some Sodium form extracellular space. The increase in Ca++ produces rising phase of action potential and reverses the membrane potential. In this way excitation wave or electrical waves are generated.

At regular intervals, the wave of contraction spreads all over the atria. The SA node sets the pace for the as a whole. Hence it is the heart’s pacemaker. The fibers of SA node are closely associated with atrial muscle hence action potential generated at SA node travels throughout the atria. This ultimately stimulates AV node through internodal pathway which is present in the posterior wall of septum of right atrium.

Atrioventricular node (AV node) is a small mass of neuromuscular tissue located in the wall of atrial septum near atrio-ventricular valves. At AV node impulse is delayed for about 0.1 sec allowing the atria to complete their contraction before the ventricles contract. The AV node is also capable of initiating impulses of contraction but at slower rate than SA node.

Atrioventricular bundle / AV bundle / Bundle of His is a mass of specialized fibers originating from AV node. AV bundle crosses the fibrous ring that separate atria and ventricle. And divides into right and left branches at upper end of septum. Within the ventricular myocardium these branches breaks down into fine purkinje fibers. Purkinje fibers convey impulses of contraction from AV node to the apex of myocardium where the wave of ventricular contraction begins and sweeps upwards, pumping blood into pulmonary artery and aorta.

Regulation of Heartbeat

Heartbeat is regulated by both hormonal and nervous control 1. Nervous control: Heart is abundantly supplied with parasympathetic (vagus) and sympathetic nerve fibers. Impulse originated in heart is increased by Sympathetic nervous system (SNS) and decreased by parasympathetic nervous system (PNS). Stimulation of right vagus slows the heart by inhibiting SA node wheres stimulation of left vagus slows AV conduction. 2. Hormonal control : The hormones adrenaline and non-adrenaline control heart activity.

ECG Don't delay your care at Mayo Clinic

• Schedule your appointment now for safe in-person care. • Learn more: Mayo Clinic facts about coronavirus disease 2019 (COVID- 19)Our COVID-19 patient and visitor guidelines, plus trusted health information • Latest on COVID-19 vaccination by site: Arizona patient vaccination updatesArizona, Florida patient vaccination updatesFlorida, Rochester patient vaccination updatesRochester and Mayo Clinic Health System patient vaccination updatesMCHS ElectrocardiogramOpen pop-up dialog box An electrocardiogram records the electrical signals in your heart. It's a common and painless test used to quickly detect heart problems and monitor your heart's health. Electrocardiograms — also called ECGs or EKGs — are often done in a doctor's office, a clinic or a hospital room. ECG machines are standard equipment in operating rooms and ambulances. Some personal devices, such as smart watches, offer ECG monitoring. Ask your doctor if this is an option for you. Products & Services

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1. Holter monitor 2. Implantable loop recorder Why it's done An electrocardiogram is a painless, noninvasive way to help diagnose many common heart problems in people of all ages. Your doctor may use an electrocardiogram to determine or detect:

• Abnormal heart rhythm (arrhythmias) • If blocked or narrowed arteries in your heart (coronary artery disease) are causing chest pain or a heart attack • Whether you have had a previous heart attack • How well certain heart disease treatments, such as a pacemaker, are working You may need an ECG if you have any of the following signs and symptoms:

• Chest pain • Dizziness, lightheadedness or confusion • Heart palpitations • Rapid pulse • Shortness of breath • Weakness, fatigue or a decline in ability to exercise The American Heart Association doesn't recommend using electrocardiograms to assess adults at low risk who don't have symptoms. But if you have a family history of heart disease, your doctor may suggest an electrocardiogram as a screening test, even if you have no symptoms. If your symptoms tend to come and go, they may not be captured during a standard ECG recording. In this case your doctor may recommend remote or continuous ECG monitoring. There are several different types. • Holter monitor. A Holter monitor is a small, wearable device that records a continuous ECG, usually for 24 to 48 hours. • Event monitor. This portable device is similar to a Holter monitor, but it records only at certain times for a few minutes at a time. You can wear it longer than a Holter monitor, typically 30 days. You generally push a button when you feel symptoms. Some devices automatically record when an abnormal rhythm is detected. An electrocardiogram is a safe procedure. There is no risk of electrical shock during the test because the electrodes used do not produce electricity. The electrodes only record the electrical activity of your heart. You may have minor discomfort, similar to removing a bandage, when the electrodes are removed. Some people develop a slight rash where the patches were placed. How you prepare No special preparations are necessary for a standard electrocardiogram. Tell your doctor about any medications and supplements you take. These can often affect the results of your test. What you can expect An electrocardiogram can be done in a doctor's office or hospital and is often done by a nurse or technician. Before You may be asked to change into a hospital gown. If you have hair on the parts of your body where the electrodes will be placed, the technician may shave the hair so that the patches stick. Once you're ready, you'll be asked to lie on an examining table or bed. During During an ECG, up to 12 sensors (electrodes) will be attached to your chest and limbs. The electrodes are sticky patches with wires that connect to a monitor. They record the electrical signals that make your heart beat. A computer records the information and displays it as waves on a monitor or on paper. You can breathe normally during the test, but you will need to lie still. Make sure you're warm and ready to lie still. Moving, talking or shivering may distort the test results. A standard ECG takes a few minutes. After You can resume your normal activities after your electrocardiogram. Results Your doctor may discuss your results with you the same day as your electrocardiogram or at your next appointment. If your electrocardiogram is normal, you may not need any other tests. If the results show an abnormality with your heart, you may need another ECG or other diagnostic tests, such as an echocardiogram. Treatment depends on what's causing your signs and symptoms. Your doctor will review the information recorded by the ECG machine and look for any problems with your heart, including:

• . Normally, heart rate can be measured by checking your pulse. An ECG may be helpful if your pulse is difficult to feel or too fast or too irregular to count accurately. An ECG can help your doctor identify an unusually fast heart rate (tachycardia) or an unusually slow heart rate (bradycardia). • Heart rhythm. An ECG can show heart rhythm irregularities (arrhythmias). These conditions may occur when any part of the heart's electrical system malfunctions. In other cases, medications, such as beta blockers, cocaine, amphetamines, and over-the-counter cold and allergy drugs, can trigger arrhythmias. • Heart attack. An ECG can show evidence of a previous heart attack or one that's in progress. The patterns on the ECG may indicate which part of your heart has been damaged, as well as the extent of the damage. • Inadequate blood and oxygen supply to the heart. An ECG done while you're having symptoms can help your doctor determine whether chest pain is caused by reduced blood flow to the heart muscle, such as with the chest pain of unstable angina. • Structural abnormalities. An ECG can provide clues about enlargement of the chambers or walls of the heart, heart defects and other heart problems. If your doctor finds any problems on your ECG, he or she may order additional tests to see if treatment is necessary. Clinical trials Explore Mayo Clinic studies of tests and procedures to help prevent, detect, treat or manage conditions. By Mayo Clinic Staff Electrocardiogram (ECG or EKG) care at Mayo Clinic Request an Appointment at Mayo Clinic Doctors & Departments April 09, 2020 Print Share on: FacebookTwitter Show references Related

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This site complies with the HONcode standard for trustworthy health information: verify here. PHYSIOLOGY OF RESPIRAION See also: Respiration (disambiguation) In physiology, respiration is the movement of oxygen from the outside environment to the cells within tissues, and the removal of in the opposite direction.[1] The physiological definition of respiration differs from the biochemical definition, which refers to a metabolic process by which an organism obtains energy (in the form of ATP and NADPH) by oxidizing nutrients and releasing waste products. Although physiologic respiration is necessary to sustain cellular respiration and thus life in animals, the processes are distinct: cellular respiration takes place in individual cells of the organism, while physiologic respiration concerns the diffusion and transport of metabolites between the organism and the external environment. Gas exchange in the occur by ventilation and perfusion.[1] Ventilation refers to the in and out movement of air of the and perfusion is the circulation of blood in the pulmonary capillaries.[1] In mammals, physiological respiration involves respiratory cycles of inhaled and exhaled breaths. Inhalation ( in) is usually an active movement that brings air into the lungs where the process of gas exchange takes place between the air in the alveoli and the blood in the pulmonary capillaries. Contraction of the diaphragm muscle cause a pressure variation, which is equal to the pressures caused by elastic, resistive and inertial components of the respiratory system. In contrast, (breathing out) is usually a passive process. The process of breathing does not fill the alveoli with atmospheric air during each inhalation (about 350 ml per breath), but the inhaled air is carefully diluted and thoroughly mixed with a large volume of gas (about 2.5 liters in adult humans) known as the functional residual capacity which remains in the lungs after each exhalation, and whose gaseous composition differs markedly from that of the ambient air. Physiological respiration involves the mechanisms that ensure that the composition of the functional residual capacity is kept constant, and equilibrates with the gases dissolved in the pulmonary capillary blood, and thus throughout the body. Thus, in precise usage, the words breathing and ventilation are hyponyms, not synonyms, of respiration; but this prescription is not consistently followed, even by most health care providers, because the term (RR) is a well-established term in health care, even though it would need to be consistently replaced with ventilation rate if the precise usage were to be followed. OXYGEN DISSOCIATION CURVE The oxygen dissociation curve is a graph with oxygen partial pressure along the horizontal axis and oxygen saturation on the vertical axis, which shows an S-shaped relationship. Oxygen and carbon dioxide are transported in the blood as a result of changes in blood partial pressures BOHR EFFECT The Bohr effect is a phenomenon first described in 1904 by the Danish physiologist Christian Bohr. Hemoglobin's oxygen binding affinity (see oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration of carbon dioxide.[1] That is, the Bohr effect refers to the shift in the oxygen dissociation curve caused by changes in the concentration of carbon dioxide or the pH of the environment. Since carbon dioxide reacts with water to [2] form carbonic acid, an increase in CO2 results in a decrease in blood pH, resulting in hemoglobin proteins releasing their load of oxygen. Conversely, a decrease in carbon dioxide

Experimental discovery[edit]

The original dissociation curves from Bohr's experiments in the first description of the Bohr effect, showing a decrease in oxygen affinity as the partial pressure of carbon dioxide increases. This is also one of the first examples of cooperative binding. X-axis: oxygen partial pressure in mmHg, Y-axis % oxy-hemoglobin. The curves were obtained using whole dog blood, with the exception of the dashed curve, for which horse blood was used. In the early 1900s, Christian Bohr was a professor at the University of Copenhagen in Denmark, already well known for his work in the field of respiratory physiology.[3] He had spent the last two decades studying the solubility of oxygen, carbon dioxide, and other gases in various liquids,[4] and had conducted extensive research on haemoglobin and its affinity for oxygen.[3] In 1903, he began working closely with Karl Hasselbalch and August Krogh, two of his associates at the university, in an attempt to experimentally replicate the work of Gustav von Hüfner, using whole blood instead of haemoglobin solution.[1] Hüfner had suggested that the oxygen-haemoglobin binding curve was hyperbolic in shape,[5] but after extensive experimentation, the Copenhagen group determined that the curve was in fact sigmoidal. Furthermore, in the process of plotting out numerous dissociation curves, it soon became apparent that high partial pressures of carbon dioxide caused the curves to shift to the [4] right. Further experimentation while varying the CO2 concentration quickly provided conclusive evidence, confirming the existence of what would soon become known as the Bohr effect.[1] Controversy[edit] There is some more debate over whether Bohr was actually the first to discover the relationship between CO2 and oxygen affinity, or whether the Russian physiologist Bronislav Verigo [ru] beat him to it, allegedly discovering the effect in 1898, six years before Bohr.[6] While this has never been proven, Verigo did in fact publish a paper on the [7] haemoglobin-CO2 relationship in 1892. His proposed model was flawed, and Bohr harshly criticized it in his own publications.[1] Another challenge to Bohr's discovery comes from within his lab. Though Bohr was quick to take full credit, his associate Krogh, who invented the apparatus used to measure gas concentrations in the experiments,[8] maintained throughout his life that he himself had actually been the first to demonstrate the effect. Though there is some evidence to support this, retroactively changing the name of a well-known phenomenon would be extremely impractical, so it remains known as the Bohr effect.[4] Physiological role[edit] The Bohr effect increases the efficiency of oxygen transportation through the blood. After hemoglobin binds to oxygen in the lungs due to the high oxygen concentrations, the Bohr effect facilitates its release in the tissues, particularly those tissues in most need of oxygen. When a tissue's metabolic rate increases, so does its carbon dioxide waste production. When released into the bloodstream, carbon dioxide forms and protons through the following reaction:

Although this reaction usually proceeds very slowly, the enzyme carbonic anhydrase (which is present in red blood cells) drastically speeds up the conversion to bicarbonate and protons.[2] This causes the pH of the blood to decrease, which promotes the dissociation of oxygen from haemoglobin, and allows the surrounding tissues to obtain enough oxygen to meet their demands. In areas where oxygen concentration is high, such as the lungs, binding of oxygen causes haemoglobin to release protons, which recombine with bicarbonate to eliminate carbon dioxide during exhalation. These opposing protonation and deprotonation reactions occur in equilibrium resulting in little overall change in blood pH. The Bohr effect enables the body to adapt to changing conditions and makes it possible to supply extra oxygen to tissues that need it the most. For example, when muscles are undergoing strenuous activity, they require large amounts of oxygen to conduct cellular − + respiration, which generates CO2 (and therefore HCO3 and H ) as byproducts. These waste products lower the pH of the blood, which increases oxygen delivery to the active muscles. Carbon dioxide is not the only molecule that can trigger the Bohr effect. If muscle cells aren't receiving enough oxygen for cellular respiration, they resort to fermentation, which releases lactic acid as a byproduct. This increases the acidity of the blood far more than CO2 alone, which reflects the cells' even greater need for oxygen. In fact, under anaerobic conditions, muscles generate lactic acid so quickly that pH of the blood passing through the muscles will drop to around 7.2, which causes haemoglobin to begin releasing roughly 10% more oxygen.[2]

The magnitude of the Bohr effect is given by , which is the slope on this graph. A steeper slope means a stronger Bohr effect. Strength of the Effect and Body Size[edit]

The magnitude of the Bohr effect is usually given by the slope of the vs curve where, P50 refers to the partial pressure of oxygen when 50% of haemoglobin's binding sites are occupied. The slope is denoted: where denotes change. That is, denotes the change in and the change in . Bohr effect strength exhibits an inverse relationship with the size of an organism: the magnitude increases as size and weight decreases. For example, mice possess a very strong Bohr effect, with a value of -0.96, which requires relatively minor changes in H+ or CO2 concentrations, while elephants require much larger changes in concentration to achieve a much weaker effect .[9]

Mechanism[edit] Allosteric interactions[edit]

Haemoglobin changes conformation from a high-affinity R state (oxygenated) to a low- affinity T state (deoxygenated) to improve oxygen uptake and delivery. The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer, a mechanism first proposed by Max Perutz in 1970.[10] Haemoglobin exists in two conformations: a high-affinity R state and a low- affinity T state. When oxygen concentration levels are high, as in the lungs, the R state is favored, enabling the maximum amount of oxygen to be bound to the hemes. In the capillaries, where oxygen concentration levels are lower, the T state is favored, in order to facilitate the delivery of oxygen to the tissues. The Bohr effect is dependent on this + allostery, as increases in CO2 and H help stabilize the T state and ensure greater oxygen delivery to muscles during periods of elevated cellular respiration. This is evidenced by the fact that myoglobin, a monomer with no allostery, does not exhibit the Bohr effect.[2] Haemoglobin mutants with weaker allostery may exhibit a reduced Bohr effect. For example, in Hiroshima variant haemoglobinopathy, allostery in haemoglobin is reduced, and the Bohr effect is diminished. As a result, during periods of exercise, the mutant haemoglobin has a higher affinity for oxygen and tissue may suffer minor oxygen starvation.[11] T-state stabilization[edit] When hemoglobin is in its T state, the N-terminal amino groups of the α-subunits and the C-terminal histidine of the β-subunits are protonated, giving them a positive charge and allowing these residues to participate in ionic interactions with carboxyl groups on nearby residues. These interactions help hold the haemoglobin in the T state. Decreases in pH (increases in acidity) stabilize this state even more, since a decrease in pH makes these residues even more likely to be protonated, strengthening the ionic interactions. In the R state, the ionic pairings are absent, meaning that the R state's stability increases when the pH increases, as these residues are less likely to stay protonated in a more basic environment. The Bohr effect works by simultaneously destabilizing the high-affinity R state and stabilizing the low-affinity T state, which leads to an overall decrease in oxygen affinity.[2] This can be visualized on an oxygen-haemoglobin dissociation curve by shifting the whole curve to the right. Carbon dioxide can also react directly with the N-terminal amino groups to form carbamates, according to the following reaction:

CO2 forms carbamates more frequently with the T state, which helps to stabilize this conformation. The process also creates protons, meaning that the formation of carbamates also contributes to the strengthening of ionic interactions, further stabilizing the T state.[2 Hypoxia[1] is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.[2] Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during hypoventilation training or strenuous physical exercise. Hypoxia differs from hypoxemia and anoxemia in that hypoxia refers to a state in which oxygen supply is insufficient, whereas hypoxemia and anoxemia refer specifically to states that have low or zero arterial oxygen supply.[3] Hypoxia in which there is complete deprivation of oxygen supply is referred to as anoxia. Generalized hypoxia occurs in healthy people when they ascend to high altitude, where it causes altitude sickness leading to potentially fatal complications: high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE).[4] Hypoxia also occurs in healthy individuals when breathing mixtures of gases with a low oxygen content, e.g. while diving underwater especially when using closed-circuit rebreather systems that control the amount of oxygen in the supplied air. Mild, non-damaging intermittent hypoxia is used intentionally during to develop an athletic performance adaptation at both the systemic and cellular level.[5] In acute or silent hypoxia, a person's oxygen level in blood cells and tissue can drop without any initial warning, even though the individual's chest x-ray shows diffuse pneumonia with an oxygen level below normal. Doctors report cases of silent hypoxia with COVID-19 patients who did not experience shortness of breath or coughing until their oxygen levels had plummeted to such a degree that the patients risked acute respiratory distress (ARDS) and organ failure.[6] In a New York Times opinion piece (April 20th, 2020), emergency room doctor Richard Levitan reports "a vast majority of Covid pneumonia patients I met had remarkably low oxygen saturations at triage—seemingly incompatible with life—but they were using their cell phones as we put them on monitors."[6] Hypoxia is a common complication of preterm birth in newborn infants. Because the lungs develop late in pregnancy, premature infants frequently possess underdeveloped lungs. To improve lung function, doctors frequently place infants at risk of hypoxia inside incubators (also known as humidicribs) that provide warmth, humidity, and oxygen. More serious cases are treated with CPAP. The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza in recognition of their discovery of cellular mechanisms to sense and adapt to different oxygen concentrations, establishing a basis for how oxygen levels affect physiological function.