So I Got Into Grad School Today With My Shitty 2.8 Gpa And The Moral Of The Story Is Reblog Those Good

Ugh #1

Fucking up when you knew you would is so funny.

Your depression is there to tell you you are a worthless piece of shit who has to fuck other people up.

But you are ready.

Anxiety already prepared you for fucking up. 😝 you knew that would happen

Anti-cancer drugs - DNA targeting

Include alkylating agents, intercalating agents, and chain cutters.

Alkylating agents

Highly electrophilic species, looking for nucleophilic sites to attack, and forming covalent bonds to bases in DNA 

Prevent replication and transcription 

Toxic side effects (e.g. alkylation of proteins) 

Bind in the major groove of DNA

Both types cross-link DNA by covalently bonding to nitrogen of base pairs.

Binding of nucleic acid bases results in miscoding and distortion. 

Distortion of DNA prevents excision by HMG proteins – permanent damage. 

Transcription and replication prevented, tumour growth slows. 

Two electrophilic sites on an anticancer drug can cause interstrand and intrastrand cross-linking.

Preference for 1,2-GG or 1,2-GC linkage sites, with interstrand or intrastrand linkage, is dictated by drug chemical structure 

Other linkage adducts are possible. Eg 1,3-GCG, 1,2-GA. 

Monofunctional adducts are also possible 

Chlormethine (a nitrogen mustard)

 Chlormethine is highly reactive, toxic side effects. 

Lead compound for many less toxic mustard derivatives. 

Methyl (CH3 ) group has positive inductive effect – promotes loss of chloride – see mechanism 

Less toxic chlormethine analogues:

Melphalan:  e- withdrawing ring lowers Nu strength of N, less reactive drug, less side effects, less toxic. Mimics PhAla, carried into cells by transport proteins. 

Uracil mustard:  Uracil ring is e-withdrawing, less reactive alkylating agent. Mimics a nucleic acid base, concentrates in fast growing cells.

Cyclophosphamide:  Most commonly used alkylating agent, Non-toxic, orally active prodrug. Acrolein associated with toxicity.

Busulfan: Causes interstrand cross-linking. Sulphonate group withdraws electrons, adjacent carbon subject to Nu attack by DNA bases. 

Dacarbazine – A diazine:  Prodrug activated by oxidation in liver, decomposes to form methyldiazonium ion. Alkylates guanine groups 

INTERCALATING AGENTS

 Aminoacridines eg Proflavine

Antibiotics - Dactinomycin

Extra binding to sugar phosphate backbone by cyclic peptide 

Intercalates via minor groove of DNA double helix 

Prevents unwinding of DNA double helix 

Blocks transcription, blocks DNA-dependent RNA polymerase 

Anthracyclines eg Doxorubicin (adriamycin) 

 Extra binding to sugar phosphate backbone by NH3 Planar rings and Anthracyclines eg Doxorubicin (adriamycin) 

Intercalates via major groove of DNA double helix 

 A topoisomerase poison - blocks action of topoisomerase II by stabilising DNA-enzyme complex 

CHAIN CUTTERS 

Calicheamicin g1 I antitumour agent 

 Nucleophilic attack on trisulphide chain starts a rearrangement process. 

This interacts with DNA to generate a DNA diradical, which reacts with oxygen, resulting in chain cutting.

Bleomycins (BLM)

Highly active head, neck, testicular cancer (Hodgkin lymphoma) 

Single and double-strand cleavage of DNA with several reduced metal ions and O2 , Fe(II) highest in vivo activity. 

Three regions - 

bithiazole DNA binding domain (DBD) locks BLM into the minor groove, 

carbohydrate domain (CHD) H-bonds BLM to sugar phosphate of DNA 

metal binding domain (MBD) bonds to Fe(II)    

Mechanism

A reaction with hydrogen peroxide gives Fe(III) and hydroxyl radicals which abstract H atoms and cut the DNA chain. 

Fe2+ + H2O2 Fe3+ + OH. + OH− Fenton mechanism 

Lungs and skin have low levels of BLM hydrolase - higher sensitivity and toxicity. Pneumonitis occurs in about 10% of patients, progresses to pulmonary fibrosis. Over-expressed in malignant cells, resistance to bleomycin    

Summary of Anti-Tumour Specificity for DNA 

Major groove alkylators 

GG interstrand - N-mustards, nitrosoureas. 

GG intrastrand - methanesulphonates. 

GC-interstrand - nitrosoureas, triazines. 

Minor groove intercalators 

GG interstrand – anthracyclines. 

GC-interstrand – actinomycins, acridines. 

Minor groove chain cutters 

GC or GT intrastrand – bleomycins 

are you a pink lemonade gay or a vanilla coke gay? sword gay or axe gay? cats and dogs gay or snakes and lizards gay? string lights gay or neon lights gay?

Antimicrobial Agents  - Cell wall inhibitors

Based on mode of action • divided into families based on chemical structure

 Modes of action Interference with: 

cell wall synthesis 

protein synthesis 

nucleic acid synthesis 

plasma membrane integrity 

metabolic pathway 

Inhibitors of Bacterial Cell Wall (peptidoglycan) Synthesis 

The Beta-lactam Family 

The Glycopeptides 

Peptidoglycan is composed of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) repeat units, and amino acids.  Each NAM is linked to peptide chain and the peptide chains are cross-linked.

β-lactams 

Includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems.

class of broad-spectrum antibiotics containing a β-lactam ring

Bacterial transpeptidase enzymes are responsible for catalysing cross-linking of the peptide chains

β-lactam ring bind to these transpeptidases – this inhibits cross-linking between peptide chains and prevents synthesis of stable PG

Cell wall synthesis ceases and the bacterial cells eventually die due to osmotic instability or autolysis. 

Glycopeptides 

Polypeptide agents - basic structural elements amino acids 

Vancomycin: 

complexes with peptide portion of peptidoglycan’s precursor units 

vancomycin is a large hydrophilic molecule able to form hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides

preventing PG transglycosylation reaction – PG precursor subunits (NAG-NAM+peptide) cannot be inserted into peptidoglycan matrix;

Vancomycin also alters bacterial-cell-membrane permeability and RNA synthesis

Uses:  serious Gram positive infections e.g. MRSA wound infection

Adverse effects:

damage to auditory nerve 

hearing loss (ototoxicity) 

“Red man/neck” syndrome - rash on face, neck, upper torso 

Me, thinking about high school:

If you're tired, read this. Please.

Hey, amigo.

It’s hard, isn’t it?

I know. Sometimes, it’s painful too.

Sometimes you really wanna give up, throw the books, hide in a corner and never take any action again.

I understand. I really do.

But I’m not here to collaborate on the pity party. I’m not going to join in on the groaning challenge, or complain about how hard it is.

First, get this though. It is hard. I won’t lie. It is worth groaning upon. Maybe one or two pity parties are affordable too.

Yet, there’s a pact we’ve make together, and I’d like to remind you of it, before we talk further. New here? We call it the Shush Pact.

Don’t do it. Don’t complain. Don’t whine. Don’t give in so easily. Don’t.

Go ahead. Make the pact. Now.

Go on! Do it.

Tell yourself, today’s hard. Tiring. But, I won’t give in to this. Nor will I complain and moan about it, and waste my energy. Not today, Amelia! Today’s not that day.

Done?

Sure?

Okay. Let’s go.

If you’re tired.

If you’re tired, exhausted of the hustle, and almost at your breaking point, I want you to remember how MUCH this means to you.

I don’t know what’s driving you nuts. Maybe it’s a math problem you just can’t crack. The presentation due next week that isn’t up to the mark. Maybe it’s 3 gigantic books you have to read up on before your next theology class. Perhaps your business has come at a standstill, and you can’t get it to grow. Or maybe you hate your job, and have finally, bravely, taken the step to work the 6 hours after you come home on building the art portfolio of your dreams, because in your heart, you’ve always been an artist. Maybe you’re juggling three jobs and working late nights to save enough money to catch the dream bus.

I don’t know. But I do know that it means a lot to you.

I know how passionate you’re about this, and how much it means to you.

And yet, you’re tired.

You’re tired of it!

You’re tired of studying so much. You’re tired of DMing every business in town, to have none reply back. You’re tired of working so much, handling so much, and you feel like you haven’t had a break since you were a kid. You’re tired of the pressure, you’re tired of the hustle and you just… wanna quit.

Don’t.

Please.

It’s hard to be positive in this dark, numb time and you’re starting to work mechanically, questioning your existence with every hour, but I have to make you understand! You’re worth this! You’re so worthy of this, my love.

Please don’t quit.

Don’t give up. It’s hard, but seal those lips, and trust your gut. I know you can make it. You’ve worked so hard for this! You’ve struggled so much, invested in so many weeks of work, and right now, at your breaking point, I want you to realise that you’re worthy. Of getting that grade, that degree, finding a job you love, your crazy ambitions of opening a flower shop… everything! All of it!

You deserve the world.

Listen to me. Open your ear and listen: you’re tired, yes. But here’s the truth. You’re not done yet.

You’ve got so much to prove to yourself. So many identities to identify yourself with. Exams to slay, jobs to get, money to make, dreams to build, people to meet and love to spread.

Listen. There’s more to this. There’s more to YOU.

Don’t give up now.

Not today.

You’re not done yet.

Tiredness will pass, and I want you to just try pushing through this. Just try. You’ll see you’re so capable of winning and it’ll blow your mind when you look back and realise the strength you truly possessed because you were able to push through.

Winning is your blood. It’s your oxygen.

Tiredness is a toxic. A poison. You’re not tired, you just think you are. When the human brain says it’s done, it’s actually got 70% more to give.

Don’t forget. Your legacy awaits. If this truly means everything to you, if you’ve already put in hundreds of hours of work into this, PUSH THROUGH! You’ve got to, because your future self deserves a better life! Don’t let them tell you that you need a break. A Hawaii vacation. They’ll say you’re getting nowhere and urge you to take a break.

You and me, we both know you don’t need one. You just needed a reminder of your capabilities.

And I’ve given you that now.

Just remember, you’re not done yet.

So fuck tiredness.

Go win.

Antimicrobial Agents - Inhibition of DNA and Protein Synthesis

Bacterial chromosome replication

DNA replication

Bacterial Topoisomerases 

maintain DNA in appropriate state of supercoiling 

cut and reseal DNA

DNA gyrase (topoisomerase II) introduces negative supercoils 

Topoisomerase IV decatenates circular chromosomes 

these are the targets of the quinolone antibacterial agents 

Quinolones

bind to bacterial DNA gyrase and topoisomerase IV after DNA strand breakage 

prevent resealing of DNA 

disrupt DNA replication and repair 

bactericidal (kill bacteria)

Fluoroquinolone is particularly useful against

Gram +ves: Staphylococcus aureus, streptococci 

Gram -ves: Enterobacteriacea; Pseudomonas aeruginosa 

Anaerobes: e.g. Bacteroides fragilis 

many applications e.g. UTIs, prostatitis, gastroenteritis, STIs 

Adverse effects

Relatively well tolerated

GI upset in ~ 5% of patients 

allergic reactions (rash, photosensitivity) in 1 - 2% of patients 

Inhibition of Bacterial Protein Synthesis 

Macrolides 

in 1952: Erythromycin was isolated as the first macrolide (Streptomyces erythreus) 

Newer macrolides: clarithromycin, azithromycin 

Structurally they consist of a lactone ring (14- to 16-membered) + two attached deoxy sugars 

Mode of action 

bind reversibly to bacterial 50S ribosomal subunit 

causes growing peptide chain to dissociate from ribosome → inhibiting protein synthesis 

bacteriostatic (stops reproduction)

Macrolides’ spectrum of activity

good antistaphylococcal and antistreptococcal activity 

treatment of respiratory & soft tissue infections and sensitive intracellular pathogens • e.g. Chlamydia, Legionella 

Adverse effects

Generally well tolerated

nausea 

vomiting 

diarrhoea 

rash 

Aminoglycosides

large family of antibiotics produced by various species of Streptomyces (“mycin”) and Micromonospora (“micin”) 

include: streptomycin, neomycin, kanamycin, gentamicins, tobramycin 

Structure = linked ring system composed of aminosugars and an aminosubstituted cyclic polyalcohol 

Mode of action of aminoglycosides

Bind irreversibly to 30S ribosomal subunit 

disrupt elongation of nascent peptide chain 

translational inaccuracy → defective proteins 

bactericidal 

Spectrum of activity 

broad spectrum; mainly aerobic G-ve bacilli (e.g. P. aeruginosa) 

used to treat serious nosocomial infections (hospital acquired infections)

First TB antibiotic

Used for cystic fibrosis 

Adverse effects

all aminoglycosides have low Therapeutic Index (only a small amount needed to become toxic)

renal damage, ototoxicity, loss of balance, nausea 

BELLAMY BLAKE IS GETTING HIS WIFE BACK

Forgot I made these quick refs once!! It’s not that you should feel obligated to portray every part of an animal correctly, but in some cases these are very unique, interesting features that very few artists are ever utilizing creatively!