NERVOUS AND ENDOCRINE SYSTEMS I). Nervous System: Structure and Function A). Major functions 1).

High-level control and integration of body systems 2). Response to external influences 3). Sensory input received by the peripheral nervous system, PNS. 4). Integrative and cognitive abilities a). Cognition and integration of sensory information are carried out by the central nervous system (CNS) B). Organization of vertebrate nervous system 1). Neuron: basic cell in the nervous system. a). Soma: cell body of neuron; site nucleus and most other cellular biochemical processes. b). Axon: a single thin projection conducting signals away from soma. i). May branch to terminate at synaptic knobs with dendrites/soma of other neurons. c). Dendrite: branched projections conducting signals from other neurons. i). Bipolar: neurons with one dendrite. ii). Multipolar: neurons with multiple dendrites. 2). The Synapse a). Junction that permits a neuron to pass an electrical or chemical signal to another cell. b). The neuron sending the signal is presynaptic; the one receiving is postsynaptic. c). Electrical synapse: pre- and postsynaptic cells connected by channels that can pass electrical current (e.g. gap junction), causing voltage changes in the presynaptic cell to induce voltage changes in the postsynaptic cell. Usually found in muscle. d). Chemical synapse: presynaptic neuron releases neurotransmitter molecules that bind to receptors on the postsynaptic cell, usually on the plasma membrane. Steps: 1. Action potential travelling along presynaptic cell until it reaches the synapse. 2. Depolarization of presynaptic membrane opens voltage-gated Ca2+ channels. 3. Ca2+ flow through presynaptic membrane, increasing interior Ca 2+ concentration. 4. High Ca2+ concentration activates a set of Ca2+-sensitive proteins attached to vesicles that contain neurotransmitters. 5. Ca2+-sensitive proteins cause the membranes of some "docked" vesicles to fuse with membrane of presynaptic cell, leading to exocytosis of neurotransmitters into the synaptic cleft, a narrow space between membranes of pre- and post-synaptic cells. 6. The neurotransmitter diffuses within the cleft. Some escapes, but some binds to chemical receptors located on the membrane of the postsynaptic cell. 7. These receptors may open ligand-gated ion channels which would either depolarize the postsynaptic cell (excitatory) or hyperpolarize it (inhibitory). 8. The neurotransmitter is either reabsorbed by the presynaptic cell (reuptake), and repackaged for future release, or else it is broken down metabolically. e). When an action potential reaches the synapse, the presynaptic neuron releases chemicals into the synaptic cleft, a thin space between the two cells involved in the synaptic knob. The postsynaptic cell takes up the chemical and responds appropriately. 3). Common neurotransmitters a). Acetylcholine (ACh): found at neuromuscular junctions (synapses between neurons and skeletal muscle). It binds to its receptor, AChR, and opens an Na+ channel that depolarizes the postsynaptic cell. Degraded by acetylcholinesterase (AChE). b). Gamma-aminobutyric acid (GABA): main inhibitory neurotransmitter in CNS. c). Serotonin, dopamine, norepinephrine

4). The Action Potential a). Short-lasting depolarization of cell potential; Key to neuron-neuron communication. b). Resting membrane potential is -70mV, interior more negative. i). Maintained by Na+/K+ ATPase: active transporter that pumps 3 Na+ out of cell and 2 K+ into the cell for every ATP hydrolyzed. ii). K+ leak channels allow K+ to leak out due to chemiosmosis. c). During the action potential, the cell is temporarily depolarized. i). The membrane depolarizes (e.g. in response to a neurotransmitter). ii). If depolarization reaches threshold (-50mV), voltage-gated sodium channels open. iii). Na+ ions flood into cell, depolarizing cell until cell becomes positively charged. iv). Voltage-gated potassium channels open and the sodium channels close. v). K+ ions floods out, repolarising cell, overshooting to about -90mV (hyperpolarized) vi). K+ leak channels and Na+/K+ ATPase restore resting potential & chemical gradient. d). All-or-none: if initial depolarization does not reach threshold, nothing happens. e). Refractory period: after an action potential the neuron becomes nonresponsive for some time before it can transit another action potential. i). Absolute: no AP can be produced regardless of strength of depolarization. This is because the voltage-gated sodium channels are inactivated and will not open yet. ii). Relative: neuron requires greater depolarization to transmit an AP. This is because the membrane is still hyperpolarized from previous AP. 5). Summation a). Neurons receive both excitatory and inhibitory signals from many sources at once. These effects are summed to determine whether the postsynaptic neuron fires an AP. b). Neurotransmitters can cause depolarization, or excitatory postsynaptic potentials (EPSP), or hyperpolarisation or inhibitory postsynaptic potentials (IPSP). c). Spatial summation involves input from multiple presynaptic cells. Algebraic summation of EPSPs and IPSPs from different areas of input, usually on the dendrites, allows the potential to reach the threshold to generate an action potential (or not). d). Temporal summationn: a single presynaptic neuron rapidly fires many action potentials so that PSP begins before a previous one ends. The amplitude of the previous potential at the point where the second begins algebraically summate, generating a potential that is overall larger than the individual potentials. 6). Myelin and Nodes of Ranvier a). Some neuron axons are covered by an electrically insulating layer called myelin. i). Produced by Schwann cells: a type of supporting, non-neuronal cell in the nervous system (glia). Many other types of glia exist. b). Myelinated regions of an axon have no ion transport, passive or active. c). Gaps in the myelin sheath are called Nodes of Ranvier. d). Myelinated axons transport action potential faster because the action potential is forced to jump from node to node rather than through entire axonsaltatory conduction. C). Sensor and effecter neurons 1). Sensory neurons carry signals from the PNS to the CNS. They are afferent (incoming). 2). Motor neurons carry signals from CNS/PNS to effector organs (muscle or glands); they are efferent (outgoing). 3).

D). Central Nervous System (CNS) 1). Spinal cord a). Bundles of nervous tissue/support cells extending from brain. b). Protected by the vertebral column and the CSF. c). Mainly serves as conduit for signals from brain to PNS, but has own circuits for simple spinal reflexes (e.g. knee jerk) and primitive processes like walking or urination. d). Four main regions i). Cervical: neck region ii). Thoracic: chest region iii). Lumbar: lower back region iv). Sacral: pelvic region. 2). Brain a). Forebrain (prosencephalon) i). Diencephalon 1. Thalamus: relaying sensation, spatial sense, & motor signals to the cerebral cortex, along with the regulation of consciousness, sleep, and alertness. 2. Hypothalamus: links CNS to the endocrine system via the pituitary gland. Controls many hormonal functions as well as primitive emotions like rage. ii). Telencephalon 1. Cerebral hemispheres: LH controls motor/sensation of right side of body and vice versa. Also LH controls speech. Together make up the cerebrum and control all voluntary behaviour and complex behaviours such as social interactions, thought, judgement, learning, working memory, and language. 2. Corpus collosum: a bundle of axons that connect the cerebral hemispheres. 3. Cerebral cortex, or the grey matter of the cerebrum, has four pairs of lobes: a. Frontal lobes: voluntary movement; problem solving; complex reasoning. b. Parietal lobes: general sensations (touch, taste, temperature, pressure) c. Temporal lobes: auditory & olfactory sensation; short term memory d. Occipital lobes: vision. b). Midbrain (mesencephalon) i). Tectum, tegmentum, and some other parts. ii). Vision, hearing, motor control, sleep/wake, arousal, and temperature regulation c). Hindbrain (rhombencephalon) i). Medulla oblongata: Involuntary functions e.g. BP, heart rate, breathing, vomiting, swallowing, etc. ii). Pons: Relays signals from the forebrain to the cerebellum; has nuclei that deal with autonomic processes like sleep, respiration, and posture; coordinates balance. iii). Cerebellum: Coordinates motor control by integrating instructions of movements from forebrain. Also involved in some cognitive and emotional functions. d). Basal ganglia: voluntary motor control, procedural learning relating to routine behaviours such as bruxism and eye movements. Lesions lead to Parkinsons Disease. e). Limbic System: involved in emotion and memory. Includes the amygdale (fear centre), the hippocampus (memory centre), and the cingulate gyrus. f). Note that the medulla oblongata, pons, and midbrain combine to make the brain stem. g). Outside of brain is grey matter (made up of soma); inside is white matter (myelinated axons). 3). Cerebrospinal fluid (CSF): clear fluid around and inside the brain and spinal cord. Acts as a "cushion" for the brain, providing a basic mechanical and immunological protection. 4). Meninges: membranes that envelope & protect CNS. Three layers: dura mater, arachnoid mater, pia mater.

E). Peripheral Nervous System (PNS) (TPR) 1). Cranial nerves: 12 pairs of nerve fibres emerging from the brain. a). Vagus nerve: 10th cranial nerve; PS innervations of all organs except adrenal glands. HR & digestion. 2). Spinal nerves: 31 pairs of nerve fibres emerging from the spinal cord. 3). Somatic: voluntary control of body movements via skeletal muscles. a). Somatic motor neurons innervate skeletal muscle cells, using ACh as their neurotransmitter, and have their soma in the brainstem or the ventral spinal cord. b). Somatic sensory neurons have a long dendrite extending from a sensory receptor; soma located in a dorsal root ganglion (a cluster of sensory neuron soma) just dorsal of the spinal cord. There is one dorsal root ganglion for each segment of the spinal cord. 4). Autonomic: mostly involuntary, visceral functions. Affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils, urination, and sexual arousal. a). Autonomic sensory neurons also have their soma in the dorsal root ganglia. b). Efferent neurons for the autonomic nervous system are also ventral. i). Preganglionic neuron: soma in brainstem/spinal cord. Send axon to synapse with postgang. neuron. ii). Postganglionic neuron: sends axon to effecter (muscle or gland). c). Sympathetic: fight or flight i). Sympathetic postganglionic neurons use norepinephrine as a neurotransmitter; their somas are located in the thoracic or lumbar regions of the spinal cord. ii). Tend to have shorter preganglionic neurons & longer postganglionic neurons. iii). Adrenal medulla: modified sympathetic postganglionic neurons. 1. Releases epinephrine/adrenaline, causing SNS physiological responses like HR. d). Parasympathetic: rest and digest i). Parasympathetic postganglionic neurons use ACh as a neurotransmitter. Their somas are located in the brainstem or in the sacral portion of the spinal cord. ii). Tend to have longer preganglionic neurons & shorter postganglionic neurons, because their ganglia tend to be very close to the effector. Organ Eye Heart Lungs Digestive tract Kidney Penis Sympathetic Dilates pupil Increases rate & force of contraction Dilates bronchioles (airways) Inhibits peristalsis (& digestion) Inhibits urination Promotes ejaculation Parasympathetic Constricts pupil Decreased rate & force Constricts bronchioles Stimulates peristalsis Stimulates urination Promotes erection/lubrication

F). Reflexes 1). Reflex: involuntary and nearly instantaneous movement in response to a stimulus. 2). Monosynaptic reflex arc has a sensory neuron, a motor neuron, and a synapse in-between. 3). Polysynaptic reflex arc one or more interneurons between sensory and motor neurons. 4). Knee jerk reflex: Striking below knee stretches sensory neuron synapsing in spinal cord. Alpha-motor neuron conducts efferent impulse back to quadriceps, triggering contraction, causing a kick. This part is monosynaptic. However, inhibitory interneuron also necessary to relax the hamstring so leg can extend. 5). The quadriceps and hamstrings form an antagonist set. When quadriceps contract and hamstrings relax, the knee extends; when quadriceps relax and hamstrings contract, the knee flexes. Therefore quadriceps are extensor muscles and hamstrings are flexor muscles. 6). Muscle spindle receptors & reflex connections form feedback loop to control muscle length. Control signal is fed to spinal neurons (error detectors) with alpha-motor neurons as a controller signalling muscle to contract. Muscle spindle endings (length & velocity sensors) sense length of muscle and transmit signal back to alpha-motor neuron, where it is compared with the control signal. If the length of the muscle is wrong, new signal is generated.

II). Nervous System: Sensory Reception and Processing (TPR) A). Proprioception (self-sense): sense of the relative position of neighbouring parts of the body. 1). Muscle spindles that sense muscle stretch are important for this. B). Somatic sensors: 1). Exteroception (external-sense) vs interoception (internal-sense). 2). Mechanoreceptors: responds to mechanical pressure or distortion. a). Pacinian corpuscles: pressure sensors in the skin b). Auditory hair cell: detects vibrations caused by sound waves; in cochlea of inner ear. c). Vestibular hair cell: detects acceleration and position rel. to gravity in inner ear. 3). Chemoreceptors: detect chemical stimuli. a). Olfactory receptors: detect airborne chemicals & facilitate smell. b). Gustatory receptors: taste buds. c). Carotid & aortic bodies: detect changes in O2, CO2 and pH in the bloodstream. 4). Nociceptors: responds to potentially damaging stimuli (e.g. pain). 5). Thermoreceptors: responds to changes in temperature. 6). Electromagnetic receptors: respond to electromagnetic radiation a). In humans, photoreceptors (rods & cones in the eyes) that respond to light 7). Adaptation: change over time in the responsiveness of the sensory system to a constant stimulus. E.g. we get used to certain scents after a while and cease to smell them. C). Olfaction (smell) 1). Olfactory receptors in the nasal cavity (nasopharynx) detect volatile chemicals. 2). Olfactory sensory neurons enter brain as olfactory nerve, which projects to the olfactory bulbs in the brain. D). Gustation (taste) 1). Taste bud: has a taste pore in the middle with taste hair that detect chemicals. 2). Five flavours a). Sweet (glucose) b). Salty (Na+) c). Bitter (basic) d). Sour (acidic) e). Umami (amino acids/nucleotides). E). Hearing 1). Ear structure a). Outer ear i). Pinna: outer portion of the ear ii). External auditory canal b). Middle ear i). Divided from outer ear by tymphanic membrane (eardrum) ii). Ossicles (small bones) 1. Malleus (hammer), incus (anvil), stapes (stirrup). c). Inner ear i). Divided from middle ear by the oval window. ii). Cochlea: spiral shaped cavity 1. Organ of Corti: core hearing organ located at the small end of the cochlea Basilar membrane, tectorial membrane, hair cells auditory receptors on basilar membrane. iii). Semicircular canals: three half-circular, interconnected tubes inside each ear iv). Utricle and saccule: balance-monitoring organs in the inner ear. 1. Utricle: static equilibrium 2. Saccule: linear acceleration.

2). Mechanism of hearing (TPR) a). Sound waves bounce off pinna external auditory canal vibration on eardrum ossicles (malleus, incus, and stapes) pass along vibrations oval window pressure waves in fluids (perilymph and endolymph) in cochlea basilar membrane of cochlea vibrates hair cells dragged against tectorial membrane ion channels in the hair cells open bipolar auditory neurons send impulses to brain b). Pitch: frequency of a sound. i). High frequencies max vibrations at basal end of the cochlear coil (near the oval window) ii). Low frequencies max vibrations at apical end (far from oval window) c). Loudness: amplitude of sound. Higher amplitude more action potentials fired. d). Balance/equilibrioception: facilitated by vestibular system (part of the ear unrelated to hearing). The semicircular canals are filled with endolymph and contains motion sensors with cilia. As skull twists, endolymph is thrown around. The cilia detect endolymph movement, &signal is sent to the brain. F). Vision 1). Light receptors (photoreceptors) a). Rods: photoreceptors in the retina that function in dimmer light than cones. Cylindrical in shape; concentrated at outer edges of the retina and used in peripheral & night vision. b). Cones: photoreceptors in the retina for color vision; function best in bright light, unlike rods. Densely packed in fovea, but sparser towards periphery of retina. Able to perceive finer detail and rapid changes in images. Humans have three kinds of cones with different photopsins trichromatic vision. c). Retinal: light-absorbing pigment in rods and cones. When light hits retinal, one of its cis alkenes is converted to trans, causing the photoreceptor cell to fire an action potential. 2). Eye structure a). Light enters cornea and is refracted by its curvature. b). Sclera: white part around cornea. Overlays a layer called the choroid which contains connective tissue. c). The retina, or light-sensitive tissue lining the inner surface of the eye, is underneath the choroid. d). Beneath the cornea is the anterior chamber, which contains the fluid aqueous humour. e). Behind this is iris, circular membrane that regulates size of pupil and thus amount of light entering eye. f). Behind the iris is the posterior chamber which also contains aqueous humour. g). Beneath posterior chamber is the lens: transparent, biconvex structure that helps to refract light to be focused on retina by changing curvature and therefore the focal distance of the eye. The ciliary muscle regulates lens curvature. h). After passing through the lens, light passes through the vitreous chamber, which contains the fluid vitreous humour before reaching the retina in the back of the eye. i). The retina has three layers: i). Light receptors (rods and cones) ii). Bipolar cells: neurons with one dendrite and one axon; send signal from photoreceptors to ganglion cells. iii). Ganglion cells: receive signal from photoreceptors via bipolar cells; axons form optic nerve visual cortex in occipital lobe. iv). Light travels through the ganglion cells and the bipolar cells first before reaching the photoreceptors. j). Where the optic nerve converges is the optic disk or blind spot no photoreceptors. k). Fovea: in middle of part of retina called macula, contains only cones, facilitates sharp/foveal vision.

3). Defects a). Emmetropia: normal vision. b). Myopia: when the lens is too much curvedtoo convergentcausing image to be focused in front of retina rather than on it. Corrected with a concave (divergent) lens. c). Hyperopia: when lens is not curved enoughtoo divergentcausing image to be focused behind retina. Corrected with a convex (convergent) lens. d). Presbyopia: lens is unable to focus due to age. 4). Visual image processing a). Information is passed through the optic nerve in each eye to the brain. The optic nerves cross at the optic chiasm to reach a series of nuclei on the contralateral sides of the brain. Eventually visual image is processed in the visual cortex in the occipital lobe. b). The visual association cortex also aids in this process. III). Endocrine System: Hormones (TPR)

A). Function of endocrine system 1). Slow physiological regulation (over the course of hours to days) 2). Specific chemical control at cell, tissue, organ levels 3). Gamete synthesis, ovulation, pregnancy, growth, sexual development, metabolism, etc. B). Definitions 1). Endocrine gland: ductless gland; secretory products are picked up by capillaries supplying blood to the region. 2). Exocrine gland: secretes into external environment via ducts that empty into gastro-intestinal lumen or outside. a). E.g. sweat glands, salivary glands, stomach, liver, pancreas. 3). Hormone: chemical released by a cell or gland that signals to other cells, often at a distance. 4). Hormone receptor: polypeptide with ligand-specific binding site; when hormone (ligand) binds, effects downstream biochemical responses. Facilitates tissue specificity of hormones. 5). Autocrine: when a cell secretes a hormone (autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cell. a). E.g. T cells secrete interleukin 2 which causes self-stimulation and proliferation of its own type of cells.

C). Major endocrine glands (names, locations, products) (TPR) Gland Hypothalamus Anterior pituitary (adenohypophysis) Tropic Hormone (class) Releasing & inhibiting factors (p) Growth hormone (GH) (p) Prolactin (p) Thyroid stimulating hormone (TSH) (p) Adrenocorticotropic hormone (ACTH) (p) Luteinizing hormone (LH) (p) Follicle stimulating hormone (FSH) (p) Melanocyte-stimulating hormones (MSH) (p) Antidiuretic hormone (ADH, vasopressin) (p) Oxytocin (p) Melantonin Thyroid hormone (TH, thyroxine) (mod. AA) Triiodothyronine (T3) (mod AA) Calcitonin (p) Parathyroid hormone (PTH) (p) Thymosin (children) (p) Epinephrine (mod. AA) Cortisol (glucocorticoid) (ster) Aldosterone (mineralocorticoid) (ster) Sex steroids Insulin ( cells secrete) (p) Glucagon ( cells secrete) (p) Somatostatin (SS- cells secrete) (p) Testosterone (ster) Estrogen (ster) Progesterone (ster) Atrial natriuretic factor (ANF) (p) Erythropoietin (p) Thrombopoietin (TPO) (p) (also produced in liver) Target/effect Anterior pituitary/modify activity bone & muscle growth; cell turnover rate Mammary gland/milk production Thyroid/ synthesis & release of TH growth & secretory activity of adrenal cortex Ovary/ovulation; testes/testosterone synthesis Ovary/follicle development; testes/spermatogenesis Skin & hair/release of melanin (pigmentation) Kidney/water retention Breast/milk letdown; uterus/contraction Regulates sleep-wake cycle; antioxidant Child: physical & mental development. Adult: metabolic rate & temp. Same as thyroxine, but with greater activity and synthesised in smaller amounts. Bone, kidney/lowers serum Ca2+ concentration Bone, kidney, small intestine/raises serum Ca 2+ concentration. T cell development during childhood Sympathetic stress response (rapid) Long term stress response; blood glucose conc.; protein metabolism; inflammatory & immunity; etc. Kidney/ Na+ reabsorption to blood pressure Not imp. But overproduction masculinisation/feminisation Blood glucose; glycogen & fat storage. Absent/ineffective in diabetes mellitus. Blood glucose; glycogen & fat storage. Inhibits many digestive processes Male characteristics; spermatogenesis Female characteristics; endometrial growth Endometrial secretion; pregnancy Kidney/ urination to blood pressure Bone marrow/ RBC synthesis Bone marrow/ platelet synthesis

Gonadotropic

Pars intermedia (pituitary) Posterior pituitary (neurohypophysis) Pineal gland Thyroid

Thyroid C cells Parathyroids Thymus Adrenal medulla Adrenal cortex

Endocrine pancreas (islets of Langerhans) Testes Ovaries/placenta Heart Kidney

D). Major types of hormones (TPR) Peptide hormones Hydrophilic; large (polypeptides) or small (amino acid deriv.) Insulin (large); catechoamines (based on tyrosine. E.g. epinephrine) Rough ER then modified in Golgi Stored in vesicles until signal for secretion leads to exocytosis Free Only target cells with appropriate surface receptors (b/c not membrane-permeable) Surface receptors generate second messenger cascade that modify enzyme activity. Rapid (minutes-hours) & short-lived Steroid hormones Hydrophobic; small (based on cholesterol) Estrogen Smooth ER Synthesized with need; used immediately, not stored Bound to protein carrier Targets cells with right cytoplasmic receptors Binds to receptors to alter gene expression by regulating DNA transcription Slow (days), long-lasting

Structure Examples Site of synthesis Regulation of release Transport in bloodstream Specificity Mechanism of effect Timing of effect IV).

Endocrine System: Mechanisms of Hormone Action

A). Cellular mechanisms of hormone action 1). Peptide hormones a). Signal transduction: extracellular signaling molecule activates a membrane receptor, in turn altering intracellular molecules to effect biochemical responses. b). The receptor can recruit second messenger to relay signal by changes in receptor c). Signal amplification: second messenger can modify many enzymes before becoming inactivated. 2). Steroid hormones a). Diffuse into cell since it is hydrophobic b). Binds to cytoplasmic receptor (a metalloprotein). c). Hormone-receptor complex enters nucleus, binds DNA sequences induces transcription. d). Can also bind to membrane receptors like peptide hormones. B). Transport of hormones (bloodstream) 1). Peptide hormones can move freely in the bloodstream. 2). Steroid hormones must bind to a plasma carrier protein to move through bloodstream e.g. albumin C). Specificity of hormones (target tissue) 1). Only cells with receptors for specific hormones will be affected. D). Feedback regulation 1). Calcitonin and serum Ca2+ concentration a). Calcitonin lowers the serum concentration of Ca2+. b). If serum [Ca2+] rises, calcitonin is secreted c). If [Ca2+] falls, calcitonin secretion is inhibited. d). Feedback loop homeostasis maintenance. 2). Cortisol regulation a). Hypothalamus secretes CRH (corticotrophin releasing factor) which stimulates the pituitary to secrete ACTH (adrenocorticotropic hormone), which, in turn, stimulates the adrenal glands to secrete cortisol b). CRH and ACTH are a tropic hormonesthose that regulate other hormones. c). ACTH feedback inhibits the pituitary. d). Cortisol feedback inhibits both the pituitary and the hypothalamus.

E). Integration with nervous system 1). Hypothalamic-Pituitary Control Axis: a). Hypothalamus secretes other releasing and inhibiting factors (tropic hormones that regulate other tropic hormones) that affect the pituitary, which secretes tropic hormones to other endocrine glands. b). Releasing and inhibiting factors are transported from the hypothalamus to the pituitary via the hypothalamic-pituitary portal system, a small circulatory system. c). The anterior pituitary is a regular endocrine gland and is regulated by releasing and inhibiting factors from the hypothalamus. i). Also called adenohypophysis. d). The posterior pituitary comprises axons from hypothalamic neurons (neuroendocrine cells), so posterior pituitary hormones are actually synthesised by soma in the hypothalamus. i). Also called neurohypophysis.