Third form of irregular verbs

CARBOHYDRATES Carbohydrates are organic compounds composed of carbon, hydrogen, and oxygen in a ratio of about one carbon atom to two hydrogen atoms to one oxygen atom. The number of carbon atoms in a carbohydrate varies. Some carbohydrates serve as a source of energy. Other carbohydrates are used as structural materials. Carbohydrates can exist as monosaccharides, disaccharides, or polysaccharides. Monosaccharides A monomer of a carbohydrate is called a monosaccharide (MAHN-oh-SAK-uh-RIED). A monosaccharide—or simple sugar— contains carbon, hydrogen, and oxygen in a ratio of 1:2:1. The gen- eral formula for a monosaccharide is written as (CH2O)n, where n is any whole number from 3 to 8. For example, a six-carbon mono- saccharide, (CH2O)6, would have the formula C6H12O6. The most common monosaccharides are glucose, fructose, and galactose, as shown in Figure 3-6. Glucose is a main source of energy for cells. Fructose is found in fruits and is the sweetest of the monosaccharides. Galactose is found in milk. Notice in Figure 3-6 that glucose, fructose, and galactose have the same molecular formula, C6H12O6, but differing structures. The different structures determine the slightly different properties of the three compounds. Compounds like these sugars, with a single chemical formula but different structural forms, are called isomers (IE-soh-muhrz). SECTION 2 OBJECTIVES ● Distinguish between monosaccharides, disaccharides, and polysaccharides. ● Explain the relationship between amino acids and protein structure. ● Describe the induced fit model of enzyme action. ● Compare the structure and function of each of the different types of lipids. ● Compare the nucleic acids DNA and RNA. VOCABULARY carbohydrate monosaccharide disaccharide polysaccharide protein amino acid peptide bond polypeptide enzyme substrate active site lipid fatty acid phospholipid wax steroid nucleic acid deoxyribonucleic acid (DNA) ribonucleic acid (RNA) nucleotide C HO H C H OH C OH H C CH2OH H C H OH O Glucose C OH C O H OH C OH H CH2OH C H CH2OH Fructose C H HO C OH H C OH H C CH2OH H C H OH O Galactose Glucose, fructose, and galactose have the same chemical formula, but their structural differences result in different properties among the three compounds. FIGURE 3-6 Copyright © by Holt, Rinehart and Winston. All rights reserved. 56 CHAPTER 3 Disaccharides and Polysaccharides In living things, two monosaccharides can combine in a condensa- tion reaction to form a double sugar, or disaccharide (die-SAK-e-RIED). For example in Figure 3-4, the monosaccharides fructose and glu- cose can combine to form the disaccharide sucrose. A polysaccharide is a complex molecule composed of three or more monosaccharides. Animals store glucose in the form of the polysaccharide glycogen. Glycogen consists of hundreds of glucose molecules strung together in a highly branched chain. Much of the glucose that comes from food is ultimately stored in your liver and muscles as glycogen and is ready to be used for quick energy. Plants store glucose molecules in the form of the polysaccha- ride starch. Starch molecules have two basic forms—highly branched chains that are similar to glycogen and long, coiled, unbranched chains. Plants also make a large polysaccharide called cellulose. Cellulose, which gives strength and rigidity to plant cells, makes up about 50 percent of wood. In a single cellu- lose molecule, thousands of glucose monomers are linked in long, straight chains. These chains tend to form hydrogen bonds with each other. The resulting structure is strong and can be broken down by hydrolysis only under certain conditions. PROTEINS Proteins are organic compounds composed mainly of carbon, hydrogen, oxygen, and nitrogen. Like most of the other biological macromolecules, proteins are formed from the linkage of monomers called amino acids. Hair and horns, as shown in Figure 3-7a, are made mostly of proteins, as are skin, muscles and many biological catalysts (enzymes). Amino Acids There are 20 different amino acids, and all share a basic structure. As Figure 3-7b shows, each amino acid contains a central carbon atom covalently bonded to four other atoms or functional groups. A single hydrogen atom, highlighted in blue in the illustration, bonds at one site. A carboxyl group, —COOH, highlighted in green, bonds at a second site. An amino group, —NH2, highlighted in yel- low, bonds at a third site. A side chain called the R group, high- lighted in red, bonds at the fourth site. The main difference among the different amino acids is in their R groups. The R group can be complex or it can be simple, such as the CH3 group shown in the amino acid alanine in Figure 3-7b. The differences among the amino acid R groups gives different proteins very different shapes. The different shapes allow pro- teins to carry out many different activities in living things. Amino acids are commonly shown in a simplified way such as balls, as shown in Figure 3-7c. (a) Many structures, such as hair and horns are made of proteins. (b) Proteins are made up of amino acids. Amino acids differ only in the type of R group (shown in red) they carry. Polar R groups can dissolve in water, but nonpolar R groups cannot. (c) Amino acids have complex structures, so, in this and other textbooks, they are often simplified into balls. FIGURE 3-7 (b) Alanine (an amino acid) (c) Simplified version of amino acid CH3 H N OH C C H O H (a) Copyright © by Holt, Rinehart and Winston. All rights reserved. BIOCHEMISTRY 57 H H N C C OH H O H CH3 H2O Glycine Alanine H N OH C C H O H H H N C C H O H CH3 N OH C C H O H (a) (b) (a) The peptide bond (shaded blue) that binds amino acids together to form a polypeptide results from a condensation reaction that produces water. (b) Poly- peptides are commonly shown as a string of balls in this textbook and elsewhere. Each ball represents an amino acid. FIGURE 3-8 Substrate Products Enzyme 1 2 3 In the induced fit model of enzyme action, the enzyme can attach only to a substrate (reactant) with a specific shape. The enzyme then changes and reduces the activation energy of the reaction so reactants can become products. The enzyme is unchanged and is available to be used again. 3 2 1 FIGURE 3-9 Dipeptides and Polypeptides Figure 3-8a shows how two amino acids bond to form a dipeptide (die-PEP-TIED). In this condensation reaction, the two amino acids form a covalent bond, called a peptide bond (shaded in blue in Figure 3-8a) and release a water molecule. Amino acids often form very long chains called polypeptides (PAHL-i-PEP-TIEDZ). Proteins are composed of one or more polypep- tides. Some proteins are very large molecules, containing hun- dreds of amino acids. Often, these long proteins are bent and folded upon themselves as a result of interactions—such as hydrogen bonding—between individual amino acids. Protein shape can also be influenced by conditions such as temperature and the type of solvent in which a protein is dissolved. For exam- ple, cooking an egg changes the shape of proteins in the egg white. The firm, opaque result is very different from the initial clear, runny material. Enzymes Enzymes—RNA or protein molecules that act as biological catalysts—are essential for the functioning of any cell. Many enzymes are proteins. Figure 3-9 shows an induced fit model of enzyme action. Enzyme reactions depend on a physical fit between the enzyme molecule and its specific substrate, the reactant being catalyzed. Notice that the enzyme has folds, or an active site, with a shape that allows the substrate to fit into the active site. An enzyme acts only on a specific substrate because only that substrate fits into its active site. The linkage of the enzyme and substrate causes a slight change in the enzyme’s shape. The change in the enzyme’s shape weakens some chemical bonds in the substrate, which is one way that enzymes reduce activation energy, the energy needed to start the reaction. After the reaction, the enzyme releases the products. Like any catalyst, the enzyme itself is unchanged, so it can be used many times. An enzyme may not work if its environment is changed. For example, change in temperature or pH can cause a change in the shape of the enzyme or the substrate. If such a change happens, the reaction that the enzyme would have catalyzed cannot occur.

LESSON 4. Cellular Respiration • Define cellular respiration • Identify the stages of clan respiration You have just learned how the energy from the sun is captured, processed, and stored in the form of glucose. Cellular respiration, another important life process, is the means by which cells release the stored energy in glucose to make adenosine triphosphate (ATP). The primary goal of this life process is to convert stored energy into usable form, such as ATP, for the cells to carry out their functions. Cellular respiration involves several chemical reactions. The reactions can be summed up in the following equation: C6 H12 O6 + 602 ----- 6 CO₂ +6H₂O + ATP Glucose oxygen carbon dioxide water energy Aerobic respiration reactions, or cellular respiration that takes place in the presence of oxygen, can be grouped into three stages glycolysis, Krebs cycle, and electron transport chain (ETC). Stage 1: Glycolysis Glycolysis is the process that breaks down one molecule of 6-C glucose into 3-C pyruvates or pyruvic acids. It also releases four molecules of ATP. This process occurs in the cytoplasm of the cell. The following is the step-by-step process of glycolysis. Take note that several enzymes are involved in this process. 1. The first step of glycolysis requires energy. It can only proceed when the two ATP molecules donate energy to the glucose by transferring a phosphate group with the help of an enzyme, producing glucose 6-phosphate 2. Then, a specific enzyme promotes the rearrangement of the atoms, producing the fructose 6-phosphate. 3. The action of the enzyme in step 2 promotes the transfer of a phosphate group from another ATP molecule, forming fructose 1,6-bisphosphate. 4. The resulting fructose 1,6-bisphosphate molecules, with the help of another enzyme, splits into two molecules, each with three carbon backbones. These two sugars are dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. 5. Another important enzyme then rapidly interconverts the molecules of dihydro-xyacetone phosphate and glyceraldehyde 3-phosphate. This produces two molecules of glyceraldehyde 3-phosphate or 3-phosphoglyceraldehyde (PGAL) 6. The succeeding step involves another enzyme-mediated action. The hydrogen (H) from PGAL is transferred to the oxidizing agent, nicotinamide adenine dinucleotide (NAD), which forms NADH. A phosphate (P) is also added from the cytosol of the cell to oxidize the two molecules of PGAL, forming two 1.3-bisphosphoglycerate. 7. A phosphate (P) from 1,3-biphosphoglycerate is transferred to ADP to form ATP. This happens for each of the two 1,3-bisphosphoglycerate. resulting to a yield of two ATP and two 3-phosphoglycerate molecules. 8. A phosphate is transferred from 3-phosphoglycerate molecules from the third carbon to the second carbon, forming 2-phosphoglycerate molecules A hydrogen atom and a hydroxyl ((OH) group is released, which then combines to form water (H2O). The removal of H2O from 2-phosphoglycerate results in the formation of 2- phosphoglycerate molecules. 9. A hydrogen atom and a hydroxyl ((OH) group is released, which then combines to form water (H2O). The removal of H2O from 2-phosphoglycerate results in the formation of two phosphoenolpyruvic acid (PEP) 10. Phosphate (P) from PEP is transferred to ADP (and forms ATP) and the final product, pyruvic acid. This reaction yields two molecules of pyruvic acid and two ATP molecules In summary, a single glucose molecule that undergoes the process of glycolysis produces two molecules of pyruvic acid, four molecules of ATP, two molecules of NADEL and two molecules of H.O. However, only two molecules of ATP are counted as net products since two molecules of ATP are spent throughout the process. Stage II: Krebs Cycle The Krebs cycle, named after its proponent Sir Hans Adolf Krebs, is a cyclical series of enzyme-controlled reactions. This stage of cellular respiration occurs in the matrix of the mitochondria. It is sometimes. called the citric acid cycle (CAC) since it produces citric acid. Citric acid contains three carboxyl (COOH) groups; hence, it is also called the tricarboxylic acid cycle (TCA). This requires the pyruvic acids produced during glycolysis. The main function of this cycle is to produce high-energy-yielding molecules, namely, NADH and flavin adenine dinucleotide (FADH) that will later on be used in the electron transport chain reaction. Figure 6-7. Summary of glycolysis and corresponding products in each reaction presented (See Appendix F on page 285 for an enlarged and complete version of the image.) An initial process is needed for the Krebs cycle to begin. As a pyruvate molecule from glycolysis enters the mitochondrion, it undergoes an important preliminary ate to form acetyl-CoA reaction. Coenzyme-A (COA) combines with pyruvate help of an enzymatic complex. This conversion also produces CO, and NADH. The Krebs cycle is summarized as follows. Take note that several enzymes are involved in this process. 1. The Krebs cycle technically begins when the acetyl-CoA combines with oxaloacetic acid (OAA), a 4-C molecule, to produce citric acid, a 6-C molecule. 2. With the aid of an enzyme, the citric acid now goes through a series of reactions that releases energy. Water molecule is removed from the citric acid and is returned in a different location. The-OH group is repositioned, forming the molecule isocitrate. 3. Isocitrate is then oxidized, forming the a-ketoglutarate, a 5-C molecule. The byproducts of this reaction are NADH and CO, 4 The a-ketoglutarate loses its CO, and a coenzyme-A is added in its place. The decarboxylation occurs with the help of NAD, which then becomes NADH. The resulting molecule is called succinyl-CoA. 5. Succinyl-CoA is converted into succinate. Also in this reaction, a molecule of guanosine triphosphate (GTP) is synthesized. The GTP molecule has similar structure and energy properties to that of ATP and is used by cells the same way. The free phosphate group attacks the succinyl-CoA molecule, which detaches the COA. Then, phosphate is attached to GDP to come up with GTP, similar to the process that occur in ATP synthesis (from ADP to ATP). 6. Two hydrogens are removed from succinate, A molecule of flavin adenine dinucleotide (FAD), a coenzyme similar to NAD, is reduced to FADH, as it takes the hydrogens from the succinate. This reaction produces the fumarate. 7. Fumarate is then converted into malate as the addition of a water molecule is catalyzed. The final reaction is the regeneration of oxaloacetate. The resulting byproduct of this regeneration is NADH Recall that two pyruvate molecules were produced during glycolysis, causing the Krebs cycle to turn twice. Each tuts produces three molecules of NADH, single ATH one FADIH, and the by-product CO, which is exhaled. Stage III: Electron Transport Chain The electron transport chain (ETC) is a series of photon pumps on the inner membrane of the mitochondrion. Electron transport is the last stage of the cellular respiration. In this stage, the energy from NADH and FADH, from the Krebs cycle is transferred to ADP to produce ATP. This process is generally known as oxidative phosphorylation. This energy coupling mechanism in the cell was revealed by the work of Peter stored energy in the form of proton (1) gradient to phosphorylate (add phosphate) ADP and produce ATP. The pumping of hydrogen sons across the inner membrane creates higher concentration ions in the inner membrane than on the outside of the membrane. This chemiosmotic gradient causes the ions to flow back across the membrane where the concentration of ions is lower. ATP synthase lined in the matrix serve as a channel protein, helping the ions to move across the membrane. The chemiosmotic gradient powers the phosphorylation of ADP to ATP, which also occurs in the ATP synthase. After passing through the ETC, the oxygen, being the final hydrogen acceptor, combines with two electrons and two protons, forming a water molecule. Water is a by-product of cellular respiration and is excreted. MINI TEST 6-3 1. Which energy-releasing pathway yields the most ATF in each glucose molecule? 2. Briefly describe the two stages of aerobic respiration that follow glycolysis: (a) Krebs cycle (b) Electron transport chain Anaerobic Respiration Most cells carry out arrobic respiration when oxygen is present. Aerobic respiration is an efficient process that yields a lot of ATP. However, many organisms thrive in mud, marshes, animal gut, canned goods, sewage treatment pond, and deep oceans where oxygen is scarce. Organisms that can live without oxygen are called anaerobes. Cellular respiration that proceeds without the presence of oxygen is called anaerobic respiration. In the event that the oxygen supply becomes low, aerobic cells also perform fermentation and lactic acid fermentation anaerobic pathways. There are two common anaerobic pathways in these cells, alcoholic fermentation and lactic acid fermentation. In alcoholic fermentation, ethyl alcohol and carbon dioxide are produced by some cells using the pyruvate from glycolysis. Each pyruvate molecule is rearranged into acetaldehyde and carbon dioxide, which is eventually released. NADII gives up electrons to acetaldehyde to form ethanol Fermentation is widely used in the industry. Yeast, a fungus used in making bread. can undergo anaerobic respiration. Bakers aux sugar, flour, water, and yeast to form the bread dough. The dough rises due to the carbon dioxide and alcohol released by the yeast cells trapped in air bubbles. Beer and wine manufacturers, we yeast to ferment the sugars in wheat and grape juice, forming alcoholic beverages such as beer and wine. In some cells, glycolysis produces two pyruvates, two NADH molecules, and two ATP molecules. Pyruvate itself becomes the final acceptor of the electrons from the NADH that produces the final product: lactate. Oftentimes, this product is called lactic acid. Human skeletal muscles can carry out fermentation when the blood cannot supply the cells with adequate oxygen during strenuous activities. When lactic acid builds up in the muscles, fatigue, burning sensation, and cramps result. Lactic acid will continue to build up until there is adequate supply of oxygen. Lactic acid is then converted back into pyruvate in the liver. Muscles also restore normal functions. Have you ever wondered why milk or cream turns sour after some time? Bacterial cells that undergo fermentation are responsible in producing lactate that turns the milk sour. These bacteria are used in manufacturing yogurt and sour milk products. Fermentation pathways do not breakdown and utilize the glucose completely. ATP is no longer produced beyond the process of glycolysis. Thus, energy produced is just enough for some single-celled organisms, or the energy can only be used by multicellular organisms for a short period.

Chapter 22 Antihypertensive Drugs Hypertension Defined (JNC-8) Pharmacology Overview 7 main categories of drugs to treat HTN Adrenergic drugs (old friend) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Vasodilators Direct renin inhibitors A. Adrenergic Drugs: 5 Subcategories and where they act A1. Adrenergic neuron blockers (central and peripheral)- we won’t talk about this A2. Alpha1 receptor blockers (peripheral) A3. Alpha2 receptor agonists (central) A4. Beta receptor blockers (peripheral) A5. Combined α and β receptor blockers (peripheral) A2. Peripherally Acting Adrenergic DrugAlpha1 Blockers (we’ve met these) Doxazosin, prazosin, alfuzosin Block alpha1-receptors which causes BP to decrease Reduces peripheral vascular resistance and BP by dilating both arterial and venous blood vessels Main Use: benign prostatic hyperplasia (BPH) Alpha1 Blockers REMEMBER Tamsulosin (Flomax)* is an α1 blocker BUT *Tamsulosin is not used to control BP, just for BPH. A3. Centrally Acting Adrenergic DrugsAlpha 2 agonist Clonidine and methyldopa 1- Stimulate alpha2-adrenergic receptors. in the brain Decreases sympathetic outflow from the CNS which decreases NE production 2. Stimulate alpha2-adrenergic receptors in kidneys remember alpha 2 opposes alpha 1 Dilates peripheral blood vessels → lowers peripheral resistance → Results in decreased BP So ….Clonidine (Catapres) Used primarily for its ability to decrease blood pressure in an urgent setting Also use in opioid withdrawal as previously discussed Oral (multiple times a day), and topical patch formulations Do not stop abruptly as it may lead to rebound hypertension In reality, Clonidine and methyldopa Not prescribed as first-line home antiHTN drugs High incidence of unwanted adverse effects: orthostatic hypotension, fatigue, and dizziness MIGHT be uses as adjunct drugs after other drugs have failed, in conjunction with other antiHTN such as diuretics A4. Adrenergic Drugs Selective Beta 1 Blockers Metoprolol, Atenolol Reduction of HR through β1 receptor blockade (remember adrenergic blocking of this receptor???) HR results in BP Cause reduced secretion of renin = BP A4. Adrenergic Drugs Selective Beta1 Blockers Nebivolol (Bystolic) Uses: hypertension and HF Action: blocks β1 receptors and produces vasodilatation, which results in a decrease in SVR High doses loses selectivity and blocks both β1 and β2 Less sexual dysfunction All BB- Do not stop abruptly; must be tapered over 1 to 2 weeks A4. Adrenergic Drugs NONSelective Beta Blockers Propranolol Acts equally on β1 and β2 Other uses include situational anxiety associated with public speaking, test taking As mentioned on previous slide, nebivolol at high doses becomes beta nonselective A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Dual antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and vasodilation (alpha1 receptor blockade) Examples are carvedilol (common) and labetalol (not as common) A5. Dual-Action Adrenergic Drugs α1 and β Receptor Blockers Carvedilol (Coreg) Widely used drug that is well tolerated Uses: HTN, mild to moderate HF in conjunction with digoxin, diuretics, and ACE inhibitors Contraindications: severe bradycardia or unstable HF, bronchospastic conditions such as asthma, and various cardiac conduction problems Adrenergic Drugs Indications - HTN But also for Glaucoma (topical) BPH: doxazosin, prazosin, and terazosin (2 for 1) Management of severe HF when used with cardiac glycosides and diuretics Contraindications Acute HF- have to stabilize first MOAIs- yeah doesn’t everything interact with MAOIs? Peptic ulcers Severe liver/kidney disease Asthma (with beta blockers) Adrenergic Drugs: Adverse Effects Orthostatic hypotension 1st-dose syncope Rebound hypertension with abrupt discontinuation Most common: Dry mouth, drowsiness, constipation, sedation Interactions- always check for specific drug interactions Can cause additive CNS depression with alcohol, benzodiazepines, opioids Question #1 When administering an alpha-adrenergic drug for hypertension, it is most important for the nurse to assess the patient for the development of what response? Hypotension Hyperkalemia Oliguria Respiratory distress Answer A Hypotension This is a key point in patient education These drugs have strong vasodilating properties and may cause severe hypotension, especially at the beginning of therapy. B. Angiotensin-Converting Enzyme Inhibitorsaka ACE Inhibitors or ACEi Large group of safe and effective drugs Currently are 10 ACEi Often used as first-line drugs for HF and hypertension May be combined with a thiazide diuretic, loop diuretic, or Calcium Channel Blocker (CCB) You need to understand the basics ACE Inhibitors: Review RAAS ACE converts angiotensin I, formed through the action of renin, to angiotensin II Angiotensin 2 is a potent vasoconstrictor and also induces aldosterone secretion by the adrenal glands Aldosterone stimulates sodium resorption (H20 follows Na Both act to raise BP which causes kidneys to reduce renin production ACEi= Great drug to treat HTN BUT contraindicated in pregnancy (2nd,3rd trimester due to fetal renal damage) and breastfeeding first few weeks after birth B. ACE Inhibitors - PRIL Lisinopril (Prinivil) super common, often the 1st drug Enalapril (Vasotec) also common Captopril (Capoten) great if liver disease present Benazepril (Lotensin) Fosinopril (Monopril) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Primary Effects of the ACE Inhibitors Prevent Na (and H2O) resorption by inhibiting aldosterone secretion (volume reduction) (GO BACK TO RAAS DIAGRAM) blood volume decreases work of the heart preload, or the left ventricular end-diastolic volume which is important in HF ACE SUMMARY OF ACTIVITY 1) Prevent vasoconstriction caused by angiotensin 2 (2) Prevent aldosterone secretion  less sodium and water resorption Cardioprotective Effects of ACEi They slow progression of left ventricular hypertrophy (ventricular remodeling) after MI so considered cardioprotective ACE inhibitors have been shown to decrease morbidity and mortality in patients with HF Renal Protective Effects of ACEi ACE inhibitors: reduce glomerular filtration pressure by volume reduction Cardiovascular drug of choice for patients with diabetes since it helps protect kidneys by reducing pressure. Sometimes used low dose for kidney protection with DM without HTN B. ACEi Enalapril (Vasotec) Only ACEi available in both oral and IV Enalapril IV does not require cardiac monitoring Oral enalapril: prodrug (metabolized in liver) Improves patient’s chances of survival after an MI Reduces the incidence of HF B. ACEi Captopril (Capoten) Uses: prevention of ventricular remodeling after MI; reduce the risk of HF after MI Shortest half-life Must be administered multiple times throughout the day so this limits its use Not a prodrug so good for patient with liver disease Question #2 A patient with diabetes has a new prescription for the ACE inhibitor lisinopril. She questions this order because her provider has never told her that she has hypertension. What is the best explanation for this order? The doctor knows best The patient is confused This medication has cardioprotective properties This medication has a protective effect on the kidneys for patients with diabetes Answer D ACE inhibitors have been shown to have a protective effect on the kidneys because they reduce glomerular filtration pressure. This property makes them the cardiovascular drug of choice for patients with diabetes. Question #3 A patient with a history of pancreatitis and cirrhosis is also being treated for hypertension. Which drug will most likely be ordered for this patient? Clonidine Prazosin Diltiazem Captopril Answer D Captopril Captopril is not a prodrug; therefore, it does not need to be metabolized by the liver to be effective. This is an advantage in patients with liver disease. ACE Inhibitors: Adverse Effects *Dry, nonproductive cough, which reverses when therapy is stopped. This is a class effect Dizziness- Note: First-dose hypotensive effect may occur Headache & Fatigue Possible hyperkalemia ** Angioedema: rare but potentially fatal Not safe in pregnancy-are contraindicated during the second and third trimesters of pregnancy because of increased risk of fetal renal damage C. Angiotensin II Receptor Blockers(ARB) Considered an alternative to ACEi Less likely to cause a dry cough and hyper K+ that is common with ACE inhibitors Angiotensin II Receptor Blockers: Mechanism of Action Go back to RAAS diagram! ARBs affect primarily 2 places 1. Vascular smooth muscle - blocks vasoconstriction 2. Adrenal gland -Selectively blocks the binding of Ang 2 to certain Ang 2 receptors inhibiting secretion of aldosterone Lowers volume retention and BP Angiotensin II Receptor Blockers -ARTAN Losartan (Cozaar)- very common Eprosartan (Teveten) Valsartan (Diovan) Irbesartan (Avapro) Candesartan (Atacand) Olmesartan (Benicar) Telmisartan (Micardis) Azilsartan (Edarbi) C. ARB Losartan (Cozaar) Beneficial in patients with HTN and HF Used with caution in patients with kidney or liver dysfunction and in patients with renal artery stenosis ***Not safe for breastfeeding women and should not be used in pregnancy (Cat C 1st trimester, Cat D 2nd-3rd trimester), potential fetal toxicity Appear to be equally effective for the treatment of hypertension and well tolerated ARBs less likely to cause cough and hyperK+ but can still happen Evidence that ARBs are associated with lower mortality after MI than ACE inhibitors Never take ACEi and ARBs at the same time* 5. Calcium Channel Blockers (CCB) Primary use: HTN, angina, some dysrhythmias Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction Results in: Relaxed blood vessels to the heart Decreased peripheral smooth muscle tone Decreased SVResistance Decreased BP E. Diuretics First-line antiHTN in JNC 8 guidelines Decreases fluid volume The results from diuresis: preload, Peripheral resistance Overall effect  Decreased workload of the heart and decreased BP Thiazide diuretics are the most commonly used diuretics for HTN Ie hydrochlorothiazide (HCTZ), chlorthalidone We will discuss diuretics further in the chapter on diuretics F. Vasodilators Directly relax arterial or venous smooth muscle (or both) Results in: Decreased SVR Decreased afterload Peripheral vasodilation Indicated for treatment of HTN May be used in combination with other drugs F. Vasodilators Hydralazine (Apresoline) Orally: routine cases of essential hypertension Injectable: hypertensive emergencies BiDil: specifically indicated as an adjunct for treatment of HF in African-American patients F. Vasodilators Sodium Nitroprusside (Nitropress) *Sodium nitroprusside and IV diazoxide are reserved for the management of hypertensive emergencies. Contraindications: severe HF, known inadequate cerebral perfusion (especially during neurosurgical procedures) F. Vasodilators Adverse Effects Hydralazine: dizziness, headache, tachycardia, edema, dyspnea, N/V/D, vitamin B6 deficiency, rash Sodium nitroprusside: hypotension, bradycardia, decreased platelet aggregation, rash G. Direct Renin Inhibitors Aliskirin (Tekturna) Blocks the RAS pathway at the point of activation. Inhibiting renin production prevents the downstream production of Ang II (potent vasoconstrictor) Adverse effects: N/V, severe hypotension, hyponatremia, hyperkalemia… Contraindicated in patients with DM taking ACEi or ARB Miscellaneous Antihypertensives Eplerenone (Inspra) Newer class of drugs called selective aldosterone blockers (remember RAAS?) Reduces BP by blocking the actions of aldosterone at its corresponding receptors in the kidney, heart, blood vessels, and brain Indications: routine treatment of hypertension and for post-MI HF Contraindicated if serum potassium levels are high (above 5.6 mEq/L) A Special Form of HTNTreatment of Pulmonary Hypertension Sildenafil and Tadalafil Commonly used for erectile dysfunction Used for pulmonary hypertension but with different trade names Sildenafil: Revatio* (Viagra for ED) Tadalafil: Adcirca* (Cialis for ED)

In this video we take a look at the 0:02 fetch to code 0:03 execute cycle including its effect on 0:06 the various registers we've previously 0:12 [Music] 0:14 discussed a computer is defined Definition 0:17 as an electronic device that takes an 0:20 input 0:22 processes data 0:25 and delivers output 0:29 in this simple example you can see we're 0:31 taking the input 5 0:35 we're multiplying it by 2 that's our 0:37 process 0:39 and we're outputting 10. 0:44 but this could be way more complex for 0:46 example of a game console 0:48 the input could be the buttons you press 0:50 on a controller 0:53 the processes would then be carried out 0:55 by the console itself 0:59 and the output would be some form of 1:01 update to a monitor 1:02 and sound out for a speaker possibly 1:04 vibration feedback through the 1:06 controller 1:10 to process data a computer follows a set 1:13 of instructions 1:14 known as a computer program 1:18 if we take the lid off a typical desktop 1:20 computer we can identify 1:22 two critical components the memory 1:26 that stores the program and the central 1:29 processing unit or processor 1:31 which is under this large fan and 1:33 carries out the instructions 1:37 a computer carries out its function by 1:40 fetching 1:41 instructions decoding them and then 1:43 executing them 1:44 in a continuous repetitive cycle 1:46 billions of times a second 1:48 let's look at each of these stages in a 1:50 little more detail Fetch 1:53 so let's start with the fetch stage the 1:55 very first thing that happens 1:57 is the program counter is checked as it 2:00 holds the address 2:01 of the next instruction to be executed 2:07 the address stored is then copied into 2:09 the memory address register 2:14 the address is then sent along the 2:16 address bus to main memory 2:18 where it waits to receive a signal from 2:21 the control 2:22 bus so it knows what to do 2:27 as we want to read the data that's 2:29 stored in memory address 2:30 0 0 0 0 the control unit sends 2:34 a read signal along the control bus to 2:36 main memory 2:41 now main memory knows the data needs to 2:44 be read 2:45 the content stored in memory address 000 2:49 can be sent along the data bus to the 2:51 memory data register 2:56 now as we're currently in the process of 2:58 fetching an instruction 3:00 the data received by the memory data 3:03 register gets copied 3:04 into the current instruction register 3:11 the instruction effectively has now been 3:14 fetched from memory 3:16 just before we proceed to the decode 3:18 phase we now 3:19 increment the program counter so that 3:22 the address it contains 3:24 points to the address of the next 3:26 instruction which will need to be 3:30 executed 3:32 the instruction now being held in the 3:33 current instruction register 3:35 is ready to be decoded 3:39 now as we mentioned in the previous 3:41 video the instruction is made up of two 3:43 parts 3:44 we have the op code that's what it is we 3:47 need to do 3:50 and we have the operand what are we 3:53 going to do it to 3:55 now the operand could contain the actual 3:57 data 3:58 or indeed it could contain an address of 4:01 where the data is to be found 4:06 by decoding this instruction we can see 4:08 the operation we need 4:10 is a load operation so we need to load 4:14 the contents of memory location0101 4:18 into the cpus accumulator 4:25 in the exam a simple model will be used 4:27 to describe the 4:29 structure of any given instruction 4:32 you're not going to be expected to 4:34 define how an opcode is made up 4:36 but simply to interpret opcodes in the 4:39 given context of an exam 4:40 question in the example here 4:44 you can see there's a total of 16 4:46 different opcodes available 4:48 and this is because we're using four 4:50 bits for our representation 4:56 so now we've fetched the instruction and 4:59 we've decoded it so we know what we need 5:00 to do 5:01 we're finally ready to execute it 5:05 so we now send address 0101 5:08 to the memory dress register 5:13 now we're in the memory address register 5:15 we can finally send the address 5:18 down the address bus to main memory 5:24 this time we want to read the data 5:26 that's stored in memory 5:28 and so the control unit again sends a 5:30 read signal along the control bus 5:36 so main memories now receive an address 5:38 and a read signal 5:40 so the content stored at memory location 5:43 0101 5:44 can now be sent along the data bus back 5:46 to the cpu 5:47 and into the memory data register 5:54 finally the contents of the memory data 5:56 register are copied to the accumulator 5:59 and this is one of a number of general 6:00 purpose registers found in the cpu 6:04 this first instruction is now complete Branching 6:11 so what does this program actually do 6:14 you should be able to work it through 6:16 carefully and figure it out 6:19 we're now pointing instructions zero 6:21 zero zero one in the program counter 6:23 and we're ready to fetch the second 6:25 instruction 6:27 at the end of this video we're gonna 6:29 provide you with the answer 6:34 so let's talk a second about programs 6:37 that branch 6:40 on the left here we have a very simple 6:42 piece of pseudo code 6:44 line zero says first execute this line 6:46 of code 6:47 line 1 now execute this line and then 6:50 line 2 says 6:52 if the age is greater than 18 then 6:56 we're going to execute lines 3 and 4 6:58 otherwise 6:59 we're going to execute lines six and 7:02 seven 7:03 so this program doesn't necessarily 7:05 follow strictly in sequence from line 7:07 zero through to seven there's a chance 7:10 here the program may branch and jump 7:14 around 7:16 so we're going to pretend that this 7:17 program has been loaded into memory 7:20 each line of code on the left here has 7:23 ended up 7:24 as a location in memory now this is not 7:27 strictly how this would happen in this 7:28 one-to-one way 7:29 but for the purpose of example it's 7:31 absolutely fine 7:35 so the program counter starts by 7:37 pointing to memory address zero 7:39 and we fetch the first instruction 7:41 decode it and execute it 7:44 it then updates and tells us the next 7:47 instruction 7:48 is zero zero zero one because remember 7:50 the program counter is being incremented 7:52 so we fetch it decode it and we execute 7:55 line one of our program 7:59 we then fetch line two which in binary 8:01 is one 8:02 zero 8:06 now at this point depending on what 8:10 happens during the execution 8:11 of line two the program may be required 8:15 to fetch line three from memory or 8:18 line five from memory 8:25 so let's look at how this actually works 8:27 because we've said the program counter 8:28 simply gets incremented 8:31 well in the current instruction register 8:33 we have an instruction with the op code 8:36 0 1 1 0. 8:41 now when we look this up in the decode 8:43 unit we discover that this 8:45 code means branch always 8:51 this replaces the value held in the 8:54 program counter 8:56 with the contents of the operand that's 8:58 the second part of the instruction 9:01 from the current instruction register so 9:03 this case 9:04 one zero zero one 9:09 now when the next fetch cycle begins the 9:12 program counter is obviously checked 9:14 and as its contents have been previously 9:16 updated to a new memory location 9:19 and not simply incremented the program 9:22 effectively is able to jump 9:24 around memory 9:28 so having watched this video you should 9:30 be able to answer the following key 9:32 question 9:33 how does a cpu work 9:39 okay so let's um answer the question we 9:41 posed 9:42 earlier what did that program actually 9:48 do 9:50 so this is the first fetch to code 9:53 execute cycle 9:55 and this is the one that we ran through 9:57 in detail earlier 9:58 it effectively loaded the contents of 10:01 the memory 10:02 stored at location location0101 10:05 into the accumulator in other words 10:08 the dna number 3 is moved 10:11 from memory into the cpu 10:18 we then proceed onto the second fetch 10:20 decode execute cycle 10:23 now this one adds the contents of memory 10:27 located at 0 1 1 0 10:30 to the current contents of the 10:32 accumulator 10:34 so in other words the dna number one 10:38 because that's what's stored at address 10:40 zero one one zero 10:43 is added to the number three that was in 10:45 the accumulator 10:46 the results are stored back over the 10:48 accumulator 10:49 so effectively we've done three plus one 10:53 equals four 10:58 the third fetch to code execute cycle 11:00 stores the contents which are in the 11:02 accumulator 11:03 into memory location zero one one one 11:07 and that's because the op code the first 11:09 part of this current instruction 11:10 zero zero one one is the command to 11:13 store when we look it up in the decoder 11:15 unit 11:16 so in other words the result of the 11:17 previous calculation three plus one 11:19 equals four 11:20 is now written back into main memory 11:28 the fourth fetch decode execute cycle 11:30 outputs the contents of the accumulator 11:33 remember they were copied into main 11:34 memory but they're still held in the 11:35 accumulator 11:37 so in this simple abstraction the number 11:40 four is now 11:41 output to the user so they can see the 11:43 result of the calculation 11:49 the fifth and final fetch code execute 11:51 cycle 11:52 brings a halt to the current program 11:58 so this very simple program which has 12:01 five 12:02 fetch decode execute cycles has 12:04 performed the calculation 12:06 three plus one is then stored the result 12:09 in main memory 12:10 and displayed the result four to the 12:12 user 12:13 and in a high-level language this may 12:15 look something very similar to the 12:17 following two lines of code 12:20 sum variable equals num1 plus num2 12:24 print sum to the user 12:27 so you can start to get an appreciation 12:29 here of how the high level code you 12:32 write actually ends up being fetched 12:34 decoded 12:35 and executed inside a processor 12:38 of course your processor is doing 12:40 billions and billions of these 12:42 operations a second 12:43 which when you think about it is really 12:45 very impressive 12:52 [Music] 13:03 you. make 10 questions for a standerd of a level

Hi, I'm John Green, this is Crash Course U.S. History, and today, we're going to talk about slavery, which is not funny. 0:06 Yeah, so we put a lei on the eagle to try and cheer you up, but let's face it, this is going to be depressing. 0:10 With slavery, every time you think, like, "Aw, it couldn't have been that bad," it turns out to have been much worse. 0:14 Mr. Green, Mr. Green! But what about – 0:15 Yeah, Me from the Past, I'm going to stop you right there, because you're going to embarrass yourself. Slavery was hugely important to America. 0:20 I mean, it led to a civil war and it also lasted what, at least in U.S. history, counts as a long-ass time, from 1619 to 1865. 0:29 And yes, I know there's a 1200-year-old church in your neighborhood in Denmark, but we're not talking about Denmark! 0:35 But slavery is most important because we still struggle with its legacy. 0:38 So, yes, today's episode will probably not be funny, but it will be important. 0:42 [Theme Music] North & South economic ties 0:51 So the slave-based economy in the South is sometimes characterized as having been separate from the Market Revolution, but that's not really the case. 0:57 Without southern cotton, the North wouldn't have been able to industrialize, at least not as quickly, because cotton textiles were one of the first industrially products. 1:04 And the most important commodity in world trade by the nineteenth century, and 3/4 of the world's cotton came from the American South. 1:11 And speaking of cotton, why has no one mentioned to me that my collar has been half popped this entire episode, like I'm trying to recreate the Flying Nun's hat. 1:18 And although there were increasingly fewer slaves in the North as northern states outlawed slavery, cotton shipments overseas made northern merchants rich. 1:26 Northern bankers financed the purchase of land for plantations. 1:29 Northern insurance companies insured slaves who were, after all, considered property, and very valuable property. 1:35 And in addition to turning cotton into cloth for sale overseas, northern manufacturers sold cloth back to the South, where it was used to clothe the very slaves who had cultivated it. 1:45 But certainly the most prominent effects of the slave-based economy were seen in the South. Slave-based agriculture in the South 1:49 The profitability of slaved-based agriculture, especially King Cotton, meant that the South would remain largely agricultural and rural. 1:56 Slave states were home to a few cities, like St. Louis and Baltimore, but with the exception of New Orleans, 2:00 almost all southern urbanization took place in the upper South, further away from the large cotton plantations. 2:06 And slave-based agriculture was so profitable that it siphoned money away from other economic endeavors. 2:11 Like, there was very little industry in the South. 2:13 It produced only 10% of the nation's manufactured goods. 2:16 And, as most of the capital was being plowed into the purchase of slaves, there was very little room for technological innovation, like, for instance, railroads. 2:23 This lack of industry and railroads would eventually make the South suck at the Civil War, thankfully. 2:27 In short, slavery dominated the South, shaping it both economically and culturally, and slavery wasn't a minor aspect of American society. Popular attitudes concerning slavery 2:35 By 1860, there were four million slaves in the U.S., and in the South, they made up one third of the total population. 2:42 Although in the popular imagination, most plantations were these sprawling affairs with hundreds of slaves, 2:47 in reality, the majority of slaveholders owned five or fewer slaves. 2:51 And, of course, most white people in the South owned no slaves at all, though, if they could afford to, they would sometimes rent slaves to help with their work. 2:57 These were the so-called yeoman farmers who lived self-sufficiently, raised their own food, and purchased very little in the Market Economy. 3:04 They worked the poorest land and, as a result, were mostly pretty poor themselves. 3:08 But even they largely supported slavery, partly, perhaps, for aspirational reasons, and partly because the racism inherent to the system gave even the poorest whites legal and social status. 3:18 And southern intellectuals worked hard to encourage these ideas of white solidarity and to make the case for slavery. 3:23 Many of the founders, a bunch of whom you'll remember, held slaves, saw slavery as a necessary evil. 3:29 Jefferson once wrote, quote, "As it is, we have the wolf by the ear, and we can neither hold him, nor safely let him go. 3:37 Justice is on one scale, and self-preservation in the other." 3:41 The belief that justice and self-preservation couldn't sit on the same side of the scale was really opposed to the American idea, 3:47 and, in the end, it would make the Civil War inevitable. 3:50 But as slavery became more entrenched in these ideas of liberty and political equality were embraced by more people, 3:55 some southerners began to make the case that slavery wasn't just a necessary evil. 3:59 They argued, for instance, that slaves benefited from slavery. 4:03 Because, you know, because their masters fed them and clothed them and took care of them in their old age. 4:07 You still hear this argument today, astonishingly. 4:09 In fact, you'll probably see asshats in the comments saying that in the comments. 4:12 I will remind you, it's not cursing if you are referring to an actual ass. 4:15 This paternalism allowed masters to see themselves as benevolent and to contrast their family-oriented slavery with the cold, mercenary Capitalism of the free-labor North. 4:26 So yeah, in the face of rising criticism of slavery, some southerners began to argue that the institution was actually good for the social order. 4:33 One of the best-known proponents of this view was John C. Calhoun, who, in 1837, said this in a speech on the Senate floor: 4:40 "I hold that, in the present state of civilization, 4:43 where two races of different origin and distinguished by color and other physical differences as well as intellectual, are brought together, 4:51 the relation now existing in the slave-holding states between the two is, instead of an evil, a good. A positive good." 4:59 Now, of course, John C. Calhoun was a fringe politician, and nobody took his views particularly seriously. 5:04 Stan: Well, he was Secretary of State from 1844 to 1845. 5:07 John: Well, I mean, who really cares about the Secretary of State, Stan? 5:10 Danica: Eh, he was also Secretary of War from 1817 to 1825. 5:13 John: All right, but we don't even have a Secretary of War anymore, so... 5:16 Meredith: And he was Vice President from 1825 to 1832. 5:19 John: Oh my god, were we insane?! 5:21 We were, of course, but we justified the insanity with Biblical passages and with the examples of the Greeks and Romans, 5:28 and with outright racism, arguing that black people were inherently inferior to whites. 5:33 And that not to keep them in slavery would upset the natural order of things. 5:37 A worldview popularized millennia ago by my nemesis, Aristotle. God, I hate Aristotle. 5:42 You know what defenders of Aristotle always say? 5:44 "He was the first person to identify dolphins." 5:47 Well, ok, dolphin identifier. 5:50 Yes, that is what he should be remembered for, but he's a terrible philosopher! Lives & experiences of enslaved people 5:53 Here's the truth about slavery: 5:55 It was coerced labor that relied upon intimidation and brutality and dehumanization. 6:00 And this wasn't just a cultural system, it was a legal one. 6:03 I mean, Louisiana law proclaimed that a slave "owes his master... a respect without bounds, and an absolute obedience." 6:09 The signal feature of slaves' lives was work. 6:12 I mean, conditions and tasks varied, but all slaves labored, usually from sunup to sundown, and almost always without any pay. 6:20 Most slaves worked in agriculture on plantations, and conditions were different, depending on which crops are grown. 6:25 Like, slaves on the rice plantations of South Carolina had terrible working conditions, 6:29 but they labored under the task system, which meant that once they had completed their allotted daily work, they would have time to do other things. 6:36 But lest you imagine this is like how we have work and leisure time, bear in mind that they were owned and treated as property. 6:42 On cotton plantations, most slaves worked in gangs, usually under the control of an overseer, or another slave who was called a "driver." 6:49 This was back-breaking work done in the southern sun and humidity, and so it's not surprising that whippings – or the threat of them – were often necessary to get slaves to work. 6:58 It's easy enough to talk about the brutality of slave discipline, but it can be difficult to internalize it. 7:03 Like, you look at these pictures, but because you've seen them over and over again, they don't have the power they once might have. 7:09 The pictures can tell a story about cruelty, but they don't necessarily communicate how arbitrary it all was. 7:14 As, for example, in this story, told by a woman who was a slave as a young girl: 7:18 "[The] overseer... went to my father one morning and said, "Bob, I'm gonna whip you this morning." 7:22 Daddy said, "I ain't done nothing," and he said, "I know it, I'm going to whip you to keep you from doing nothing," 7:28 and he hit him with that cowhide – you know it would cut the blood out of you with every lick if they hit you hard." 7:33 That brutality – the whippings, the brandings, the rape – was real, and it was intentional, because, in order for slavery to function, slaves had to be dehumanized. 7:43 This enabled slaveholders to rationalize what they were doing, and it was hoped to reduce slaves to the animal property that is implied by the term "chattel slavery." 7:51 So the idea was that slaveholders wouldn't think of their slaves as human, and slaves wouldn't think of themselves as human. 7:57 But it didn't work. Let's go to the Thought Bubble. 7:59 Slaves' resistance to their dehumanization took many forms, but the primary way was by forming families. Family, love, & religion of enslaved people 8:05 Family was a refuge for slaves and a source of dignity that masters recognized and sought to stifle. 8:10 A paternalistic slave owner named Bennet H. Barrow wrote in his rules for the Highland Plantation: 8:15 "No rule that I have stated is of more importance than that relating to Negroes marrying outside of the plantation... It creates a feeling of independence." 8:23 Most slaves did marry, usually for life, and, when possible, slaves grew up in two-parent households. 8:28 Single-parent households were common, though, as a result of one parent being sold. 8:32 In the upper South, where the economy was shifting from tobacco to different, less labor-intensive cash crops, the sale of slaves was common. 8:40 Perhaps one-third of slave marriages in states like Virginia were broken up by sale. 8:45 Religion was also an important part of life in slavery. 8:47 While masters wanted their slaves to learn the parts of the Bible that talked about being happy in bondage, 8:52 slave worship tended to focus on the stories of Exodus, where Moses brought the slaves out of bondage, 8:57 or Biblical heroes, who overcame great odds, like Daniel and David. 9:01 And, although most slaves were forbidden to learn to read and write, many did anyway. And some became preachers. 9:07 Slave preachers were often very charismatic leaders, and they roused the suspicion of slave owners, and not without reason. 9:13 Two of the most important slave uprisings in the South were led by preachers. 9:16 Thanks, Thought Bubble. 9:17 Oh, it's time for the Mystery Document? Mystery Document 9:19 We're doing two set pieces in a row? All right. [buzzing noise] [music] 9:24 The rules here are simple. 9:26 I wanted to re-shoot that, but Stan said no. 9:29 I guess the author of the Mystery Document. 9:30 If I am wrong, I get shocked with the shock pen. 9:33 "Since I have been in the Queen's dominions I have been well contented, yes well contented for sure, man is as God intended he should be. 9:40 That is, all are born free and equal. 9:43 This is a wholesome law, not like the southern laws which puts man made in the image of God on level with brutes. 9:49 O, what will become of the people, and where will they stand in the day of judgment. 9:53 Would that the 5th verse of the 3rd chapter of Malachi were written as with a bar of iron, 9:59 and the point of a diamond upon every oppressor's heart that they might repent of this evil, and let the oppressed go free..." 10:06 All right, it's definitely a preacher, because only preachers have read Malachi. 10:10 Probably African American, probably not someone from the South. 10:13 I'm going to guess that it is Richard Allen, the founder of the African Methodist Episcopal Church? 10:18 [buzzing noise] DAAAH, DANG IT! 10:19 It's Joseph Taper, and Stan just pointed out to me that I should have known it was Joseph Taper because it starts out, 10:24 "Since I have been in the Queen's dominions..." 10:27 He was in Canada. He escaped slavery to Canada. The Queen's dominions! 10:31 All right, Canadians, I blame you for this, although, thank you for abolishing slavery decades before we did. 10:36 [electric sounds] AHHH! How people resisted & escaped slavery 10:37 So, the Mystery Document shows one of the primary ways that slaves resisted their oppression: by running away. 10:42 Although some slaves like Joseph Taper escaped for good by running away to northern free states, 10:47 or even to Canada, where they wouldn't have to worry about fugitive slave laws, even more slaves ran away temporarily, hiding out in the woods or the swamps, and eventually returning. 10:55 No one knows exactly how many slaves escaped to freedom, but the best estimate is that a thousand or so a year made the journey northward. 11:01 Most fugitive slaves were young men, but the most famous runaway has been hanging out behind me all day long: Harriet Tubman. 11:07 Harriet Tubman escaped to Philadelphia at the age of 29, and over the course of her life, she made about 20 trips back to Maryland to help friends and relatives make the journey north on the Underground Railroad. 11:17 But a more dramatic form of resistance to slavery was actual, armed rebellion, which was attempted. 11:22 Now, individuals sometimes took matters into their own hands and beat or even killed their white overseers or masters. 11:27 Like Bob, the guy who received the arbitrary beating, responded to it by killing his overseer with a hoe. 11:33 But that said, large-scale slave uprisings were relatively rare. 11:36 The four most famous ones all took place in a 35-year period at the beginning of the 19th century. Slave rebellions 11:41 Gabriel's Rebellion in 1800 – which we've talked about before – was discovered before he was able to carry out his plot. 11:45 Then, in 1811, a group of slaves upriver from New Orleans seized cane, knives, and guns, and marched on the city before militia stopped them. 11:52 And in 1822, Denmark Vesey, a former slave who had purchased his freedom, may have organized a plot to destroy Charleston, South Carolina. 11:59 I say "may have" because the evidence against him is disputed and comes from a trial that was not fair. 12:05 But regardless, the end result of that trial was that he was executed, as were 34 slaves. Nat Turner's Rebellion 12:09 But the most successful slave rebellion, at least in the sense that they actually killed some people, was Nat Turner's in August 1831. 12:15 Turner was a preacher, and with a group of about 80 slaves, he marched from farm to farm in South Hampton County, Virginia, 12:21 killing the inhabitants, most of whom were women and children, because the men were attending a religious revival meeting in North Carolina. 12:27 Turner and 17 other rebels were captured and executed, but not before they struck terror into the hearts of whites all across the American South. 12:34 Virginia's response was to make slavery worse, passing even harsher laws that forbade slaves from preaching, and prohibited teaching them to read. 12:42 Other slave states followed Virginia's lead and, by the 1830s, slavery had grown, if anything, more harsh. 12:47 So, this shows that large-scaled armed resistance was – Django Unchained aside – not just suicidal, but also a threat to loved ones and, really, to all slaves. How enslaved people resisted their oppression & why it matters 12:55 But, it is hugely important to emphasize that slaves did resist their oppression. 12:59 Sometimes this meant taking up arms, but usually it meant more subtle forms of resistance, 13:03 like intentional work slowdowns or sabotaging equipment, or pretending not to understand instructions. 13:08 And, most importantly, in the face of systematic legal and cultural degradation, they re-affirmed their humanity through family and through faith. 13:16 Why is this so important? 13:17 Because too often in America, we still talk about slaves as if they failed to rise up, 13:21 when, in fact, rising up would not have made life better for them or for their families. 13:26 The truth is, sometimes carving out an identity as a human being in a social order that is constantly seeking to dehumanize you, is the most powerful form of resistance. 13:34 Refusing to become the chattel that their masters believed them to be is what made slavery untenable and the Civil War inevitable, so make no mistake, slaves fought back. 13:45 And in the end, they won. I'll see you next week. Credits 13:48 Crash Course is produced and directed by Stan Muller. 13:50 The script supervisor is Meredith Danko. 13:52 Our associate producer is Danica Johnson. 13:54 The show is written by my high school history teacher Raoul Meyer and myself. 13:57 And our graphics team is Thought Cafe. 13:58 Every week, there's a new caption to the Libertage, but today's episode was so sad that we couldn't fit a Libertage in... 14:04 UNTIL NOW! [Libertage Rock Music] 14:08 Suggest Libertage caption in comments, where you can also ask questions about today's video that will be answered by our team of historians. 14:13 Thanks for watching Crash Course, and as we say in my home town, don't forget to be abolitionist.

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