Oofta Oofta

Uncky Puncky

[i-the-throw-away-deactivated201]

“Yes, being in a female dominated field, I do know what it means to be marginalized. “

oh

my

god

omg

oh my fucking god

[freedominwickedness]

The really ugly part is they’ve actually done multiple sociological studies on this, and guess what the result is? Men in female-dominated fields aren’t marginalized at all; they get special treatment and are fast-tracked to the top, getting more credit for their work, faster promotions, and greater pay and benefits than their female colleagues.

Here’s one study. Here’s another. And another.

[momqueer]

^phenomenon known as the glass escalator

[dynastylnoire]

have you ever been around male nurses….mannnn

[sourcedumal]

Men in female dominated fields are entitled as hell. Don’t get it twisted

[greatmardini]

teaching is a female-dominated field but most principals are male

librarianship is a female-dominated field but most directors are male

[lechugaaaaadeldiablitoooo]

Cooking is female dominated but most chefs are males

[pinkcheesegreenghost-deactivate]

a large percent of hair stylists are women,  but most major hair care brands are owned by men

[goldenheartedrose]

Also a lot of female dominated fields were once male dominated and now that they’re not, the pay is lower and they’re considered less respectable fields of work.

https://www.nytimes.com/2016/03/20/upshot/as-women-take-over-a-male-dominated-field-the-pay-drops.html

[luisonte]

Steampunk Echenique.

[celtic-pyro-deactivated20230725]

crab

[xxxtictacion]

Dwarven technology has come a long way

[queerofthecastle]

@thebibliosphere tagging you because of the post you made about fantasy mobility aids

[thebibliosphere]

That is some Wild West bullshit, I love it, that is fantastic.

[chaotictimemachineblaze]

@gothicwolfy

@accessibilityfails

[headspace-hotel]

see, this is why people who don’t want disability representation in fantasy make no sense, because why would you just…not have a steampunk crab chair…when you could totally have a steampunk crab chair…does not compute…

dwarves with chronic illness ftw??? 

[accessibilityfails]

Omg this is so awesome! Does anyone know who made this?

[oofta-oofta]

Disability is a superpower, I swear

[oofta-oofta]

Semaglutide

A type 2 diabetes drug!

It has 94% homology to human GLP-1, and the modifications prolong the half-life to around one week. 

Modifications include:

Spacer & C-18 fatty di-acid - provides strong binding to albumin

Amino acid substitution (Arginine) - prevents side chain from binding at the wrong site

Amino acid substitution (Aib) - protects from DPP-4 degradation.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestinal K- and L-cells, respectively, but are immediately subject to rapid degradation. GLP-1 is found in two active forms, amidated GLP-1 (7-36) amide and glycine-extended GLP-1 (7-37), while GIP exists as a single 42 amino acid peptide. The aminopeptidase, dipeptidyl peptidase IV (DPP IV), which is found in the endothelium of the local capillary bed within the intestinal wall, is important for the initial inactivation of both peptides, with GLP-1 being particularly readily degraded. DPP IV cleavage generates N-terminally truncated metabolites (GLP-1 (9-36) amide / (9-37) and GIP (3-42)), which are the major circulating forms. Subsequently, the peptides may be degraded by other enzymes and extracted in an organ-specific manner. However, other endogenous metabolites have not yet been identified, possibly because existing assays are unable either to recognize them or to differentiate them from the primary metabolites. Neutral endopeptidase 24.11 has been demonstrated to be able to degrade GLP-1 in vivo, but its relevance in GIP metabolism has not yet been established. Intact GLP-1 and GIP are inactivated during passage across the hepatic bed by DPP IV associated with the hepatocytes, and further degraded by the peripheral tissues, while the kidney is important for the final elimination of the metabolites.

[oofta-oofta]

Drug binding to tissue macromolecules

Many drugs have more affinity to tissue than to binding proteins, so they piss off and join their fav tissue. When there is more in tissue than blood plasma, it is classed as sequestered, and for a long time it is said to be STORED! Remember, active transport can contribute to this, like L-DOPA and LNAATs.

For a GOOD example, griseofulvin binds to keratin, causing localisation and accumulation in the stratum corneum (outer skin).

For a BAD example, take thiopental: It really likes adipose tissue, which isn't great for an anaesthetic.

[oofta-oofta]

Body fluid compartments

Eww, gross

This affects the movement of drugs. Dependent on: 

tissue permeability

compartment binding

fat:water partition

pH partition

Large drugs such as heparin stay in the plasma, whereas others bind so strongly to carriers, they can’t leave the plasma, so distribute in the special plasma water swimming pool. 

Polar drugs like gentamicin can’t enter cells, and only reach the extracellular fluid. 

Lipid soluble drugs like ethanol can enter all fluid compartments,

[oofta-oofta]

Male reproductive system

Germ cells are protected by a diffusion barrier. Capillaries and cells responsible for sperm formation have tight junctions, and the luminal surface of capillary endothelials has a high expression of P-glycoprotein. Ovaries may be similar, but surprise surprise, there is less research. Scientists like their balls. 

Damn inherent misogyny in research... like bloody contraception, go look at my contraception post guys, I mean what the fuck there’s only one thing for guys on the market and its condoms with a 70% success rate. The male pill works, and is actually better because men don’t have a hormonal cycle, but its not on the market. It isn’t on the market because of side effects WHICH ARE EXACTLY THE SAME AS THOSE REPORTED BY WOMEN ON THE PILL.

It’s not just women’s responsibility to fuck up their hormones to stop the babies okay, men need to have more responsibility too. Right now, people could take it in turns to fuck up hormones. That’d be fairer, right? Come on science, move out of the dark ages mate

https://www.theguardian.com/commentisfree/2016/oct/28/sex-shared-responsibility-why-not-contraception-male-pill 

[oofta-oofta]

Blood Brain Barrier

The BBB has continuous capillaries surrounded by contractile pericytes, foot processed astrocytes, neurones and endothelia with tight junctions. 

Lipid drugs can pass transcellularly, but some are pumped back out by p-glycoprotein. 

Polar drugs can only exit through carrier-mediated transport. Salicylic acid and valproic acid use the mono-carboxylic acid transport system, and L-DOPA uses the L-system (LNAAT) for neutral L-amino acids.

L-DOPA can cross the BBB, unlike dopamine, and is then converted by DOPA decarboxylase. Carbidopa prevents this happening around the body (wasting dose and causing adverse effects) by co-administration. Carbidopa inhibits DOPA decarboxylase but cannot cross the BBB.

[oofta-oofta]

Cancer

The normal cell cycle follows this path:

G0

G1

S

G2

Mitosis.

Tumour growth

Tumour growth rate is rapid but slows due to lack of blood supply. Symptoms appear with 10(9) cells. Proto-oncogenes turn to oncogenes, causing the inactivation of tumour suppression genes.

Benign ones are slow but can be damaging to CNS. 

Malignant are rapid and metastasise

Leukaemias aren't technically cancer: it affects haemopoetic tissue by replacing healthy bone marrow and causing platelet, erythrocyte and WBC loss. 

Carcinoma affects epithelial cells

Sarcoma affects connective tissue.

Hallmarks of cancer

Self-sufficient growth signals

Insensitive to anti-growth signals

tissue invasion / metastasis

unlimited replicative potential

sustained angiogenesis

apoptosis evasion

[oofta-oofta]

Recombinant expression of drug targets

Fast pharmacological and drug screening is made possible by putting the genetic code of drug targets (channels etc) into a cheeky vector, such as a plasmid. This CONSTRUCT is then put into a cell line via TRANSFECTION. Commonly used cells are HEK-293 cells. This allows the recombinant protein to be expressed and then analysed.

E.g. graphs can be made with % max cAMP vs Log ligand.

[oofta-oofta]

Schild Plot

The Schild Plot marks log((B/A)-1) vs -log [antagonist] . 

B/A = concentration ratio. This is measured with EC50 antagonist / EC50 no antagonist (full agonist function). 

This data is found with dose-concentration curves, where the 50% maximum response is found with that level of atropine (EC50).

If the regression of the line is linear with a gradient of -1, the antagonism is competitive, at the same site of the agonist. If this is true, the x-intercept can give an estimate of the pA2 .

[oofta-oofta]

Antagonists

There are 3 kinds of antagonist:

Competitive

Non-competitive

Physiological/functional

Competitive Antagonists

Can be surmountable (reversible) or

insurmountable (irreversible, due to extremely high affinity of the formation of covalent bonds, e.g. aspirin).

Drugs rapidly associate and dissociate so this constantly changes. The effect can be measured by observing the interaction with the agonist. 

By this method, antagonist affinity is measured as Kb, with the same reasoning as Kd (agonist association constant) is measured: as in, the amount it takes to reach 50% is used as the measure.

pA2 marks the point where double the amount of agonist is needed to elicit response, due to the action of an antagonist. It is the amount of antagonist needed to necessitate double the amount of agonist to do the same job. AKA, the estimated equilibrium dissociation constant of the antagonist.

pA2 normally equates to -log(Kb), which can be analysed in a Schild Plot. 

Non-competitive Antagonists

Alternative site binding. 

Physiological/functional

Act on different receptors for opposite effects. E.g. histamine binds to H1 on bronchiolar smooth muscle to elicit contraction. Noradrenaline and salbutamol both bind to beta-2 adrenoceptors on the smooth muscle, which cause relaxation (in opposition to the action at H1). Therefore, the agonists functionally antagonise each other.

[oofta-oofta]

Intrinsic Activity

Intrinsic activity (ε) is zero in antagonists, 

less than 1 in partial agonists 

and ε=1 in full agonists.

[oofta-oofta]

Phenylephrine

Phenylephrine, aka sudafed, is a nasal decongestant.

It agonises alpha 1 adrenoceptors to contract vascular smooth muscle, making Gq and PLC be stimulated more and more. This causes PKC to be activated, inducing vasoconstriction.

Antagonists of this are prazosin and phentolamine.

[oofta-oofta]

Steroidal drugs

Adrenal steroids are created along the Hypothalamic-Pituitary-Adrenal axis, important in homeostatic/hormonal fight or flight.

The hypothalamus releases corticotrophin releasing factor. The anterior pituitary releases adrenocorticotrophin hormone. This makes the adrenal cortex produce glucocorticoids and mineralocorticoids, which provide negative feedback to the hypothalamus.

Aldosterone is a mineralocorticoid, which causes Na+ retention, K+ depletion and maintains the H2O electrolyte balance. It is produced in the bona glomerulosa and is regulated by renin (see the renin-angiotensin post). 

Progesterone also has a mineralocorticoid function.

Glucocorticoids include hydrocortisone and corticosterone. corticosterone is important in protein and carbohydrate metabolism, and hydrocortisone is a medication to replace cortisol in adrenal insufficiency or addison’s disease, as well as asthma, COPD, MS and Crohns. 

Dexamethasone

Prednisolone

[oofta-oofta]

Epilepsy

Epilepsy can be treated with carbamazepine and phenytoin, a sodium ion channel blocker. However, these anticonvulsants also promote the induction of their own CYP450 enzymes.

[oofta-oofta]

Varicosities: sympathetic innervation of smooth muscle

Varicosities remind me of varicose veins,  they're not varicose veins, they are strange neuromuscular junctions that are a bit fat, maybe because they use steroids. 

Sympathetic stimulation causes depolarisation, allowing calcium into the varicosity and forcing noradrenaline and ATP vesicles out of the varicosity. 

NA then goes to the alpha 1 receptors on smooth muscle, which is a GPCR. It binds close to the extracellular surface between the 7 transmembrane helices. They are coupled with Gq proteins and activate PLC, releasing IP3 from the PLB. IP3 attacks the endoplasmic reticulum, which releases calcium, causing contraction (remember excitation contraction coupling? Sure you do!). Any excess NA then gets taken back up again by the alpha 2 receptor on the varicosity (they're good at recycling you know).

The other way to cause contraction is via ATP. ATP interacts with the P2X purinergic receptor on smooth muscle. This addition of energy permits calcium to enter the cell, causing contraction :)

So, blocking alpha 1 receptors prevents contraction.

Prazosin

Phentolamine

Agonising alpha 1 receptors induces contraction.

Sudafed, aka Phenylephrine

blocking alpha 2 receptors induces contraction.

Yohimbine

Chlonidine

Agonising alpha 2 receptors prevents contraction.

Also, think about beta receptors too:

They are on the heart.

Propranolol is a reversible competitive antagonist.

Carazolol 

[oofta-oofta]

Adrenergic Receptors

Alpha 1 adrenoceptors activate Gq GPCRs, interacting with PLC, which causes production of IP3 and Ca2+, activating PKC and causing contraction.

Alpha 2 adrenoceptors are inhibitory, with Gi GPCRs. They inhibit Adenylate cyclase, reducing intracellular cAMP and reducing PKA.

Beta adrenoceptors, or Gs proteins, activate adenylate cyclase, increase cAMP and increase PKA, relaxing bronchiolar receptors and smooth muscle and contraction of heart muscle.

Cardiac and aortic tissues have high affinity for adrenaline, which agonises both alpha and beta adrenoceptors. However, isoprenaline can only activate cardiac tissue, as it has beta cell specificity and virtually no affect on alpha receptors. Aortic muscle responds equally to adrenaline and noradrenaline.