snake

just a flop trying to find a place in this world

[halzune]

And you'll confess why you did it, and I'll say, "Good riddance" THE SMALLEST MAN WHO EVER LIVED

[0oadios-mnzo0-deactivated202602]

[callitsnake13]

who said cats will allow you to save money

[evermoredeluxe]

Taylor, Andrea and Austin arriving at the Buccaneers at Chiefs game in Arrowhead Stadium in Kansas City, MO on November 4, 2024

[callitsnake13]

THE WAY SHE'S BLUSHING??????

[lookatmylifes]

[chaandajaan-moved]

Thanks for @byrons-simp for tagging me, I love picrew ✌️

For anyone who wants to do it: @meherunissa @desi-dark-academia @bloomingsalma @willkillforgoodmemories

Picrew here

[darkbicademia-deactivated202206]

Thanks for the tag @chaandajaan !!

Tagging: @noorunnafs @zeb-un-nisa @a-brown-darkacademic @flappydolphin @naadan-academia @sunflowervol6-hslwt and anyone who wants to do it!

[a-brown-darkacademic]

Thank you @desi-dark-academia for the tag! 🤎🧳🍃

Here she is! I want this outfit irl SO BADLY NOWWW haha

I’m tagging @wordsmithic love ya girl!!🤩

The link : https://href.li/?https://picrew.me/image_maker/649584

[fanficaddict13125-deactivated20]

I wasn't tagged but this was cute asf and I wanted to try it, so here ya go :

Awww I love mine 🥺❤️

Tagging some people who might be interested ~

@callitsnake13 @mochiffon @ashveedhathebookish @icedtea-with-lemon16 @acaemia

[callitsnake13]

THANK YOU FOR TAGGING YOURS LOOK AMAZING THIS IS ME

[biomedicool]

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 

[biomedicool]

Human reward system and addiction - Neurology

The human reward system is made up of neural structures responsible for incentive salience (desire), associative learning (primarily positive reinforcement and classical conditioning), and positive/pleasure emotions (e.g. euphoria). 

Dopamine is the primary neurotransmitter of the brain’s reward mechanisms

Most important reward pathway is the mesolimbic dopamine pathway.

This connects the ventral tegmental area (VTA) of the midbrain, to the nucleus accumbens (NAc) and olfactory tubercle, which are located in the ventral striatum 

The projections from the VTA are a network of dopaminergic neurons with co-localized postsynaptic glutamate receptors.

The NA itself consists mainly of GABAergic medium spiny neurons. 

When a rewarding stimulus, such as eating food, or direct stimulation by a drug occurs, dopaminergic neurons in the VTA are activated. These neurons project to the NAc, and their activation causes dopamine levels in the NAc to rise, activating dopamine receptors and generating a reward response, thus encouraging repetition and learning. –> any activity that resulted in a reward from your brain will therefore be one you want to repeat. This is essentially how your brain keeps you alive and reproducing.

 Another major dopamine pathway, the mesocortical pathway, also originates in the VTA but travels to the prefrontal cortex, and is thought to integrate information which determines whether a behavior will be elicited. The basolateral amygdala projects into the NAc and is thought to also be important for motivation, while the hippocampus plays a role in learning and memory. 

Even though increased dopamine in the brain reward system is generally thought to be the final common pathway for the reinforcing properties of drugs, other neurotransmitters such as serotonin are involved in the modulation of both drug self-administration and dopamine levels.  Serotonin may be important in modulating motivational factors, or the amount of work and individual is willing to perform to obtain a drug. Serotonergic neurons project both to the NA and VTA and appear to regulate dopamine release at the NA.  

Excessive intake of addictive drugs  –> repeated release of high amounts of dopamine –>increased dopamine receptor activation. 

The intrinsic purpose of an endogenous reward center is to reinforce behaviors that promote survival, so when a drug stimulates this center, drug-seeking behavior is also promoted - induced by glutamatergic projections from the prefrontal cortex to the nucleus accumbens

Prolonged and abnormally high levels of dopamine in the synaptic cleft can induce receptor downregulation, resulting in a decrease in the sensitivity to natural stimuli. 

Alongside the positive reinforcement, these withdrawal symptoms can be considered negative reinforcing factors. 

Discontinued drug use will often induce various negative responses such as chronic irritability, physical pain, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards.

Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP), (CREB), (NF-κB). Overexpression of ΔFosB in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction. This means an individuals actual genes are changed by chronic drug use to make them even more addicted  - not just a case of being able to stop when they chose. 

[wouldvebeensweet]

“Maybe what happened to you was you didn’t know where to go next and you felt confused about where you were even headed. Or maybe you felt like you didn’t fit in anywhere, in any corner of the room. Maybe you lost someone that you never thought you would lose, or maybe you lost yourself, which is the worst thing out of all of it. Um, I know that you’re going to go through more of it in your life and so am I; and people are going to say things about us that aren’t true, and I just want you in those moments to look in the mirror and understand what you are and what you are not. You are not somebody else’s opinion of you. You are not damaged goods just because you made a few mistakes in your life. You are not going nowhere just because you haven’t arrived at your final destination yet. What you are is wiser and stronger because you’ve made mistakes. What you are is brave for living your life in a daring way that would cause you to take the risks it takes to make mistakes. What you are is someone who’s walked through a bunch of rainstorms but continues to put one foot in front of the other. I think in 25 years I’m still learning every single day, but one thing I do know is that pain actually does make you stronger– and walking through a bunch of rainstorms does not make you… does not make you damaged. If you keep on going, it actually makes you clean.”

— Taylor Swift, The 1989 Tour (Detroit, MI)

[echoesinmysleep]

“So I’ve been watching you the entire night, and, um, some things that I’ve noticed – I’ve noticed that I’m not just seeing people nodding their head to the music politely. I’m seeing people, like, thrashing around and dancing so wildly, as if absolutely no one is watching you. Like no one’s around – you’re just, like, in your bedroom jamming. Um, I’m also not just seeing people mouth the lyrics – I’m hearing people screaming every single word so loudly. And let me tell you why that makes me so happy, because that kind of behaviour is free, and uninhibited, and warm – the way you treat us is open and welcoming. And, you know, these days there are millions of ways for people to tell you how to be, how to act in public, what’s cool, what’s not cool, what’s beautiful, what’s not. And it’s really easy to become completely preoccupied by the idea of trying to be cool. You have a lot of people who will try and make you feel like being cool is being unaffected, and unexcited, and cynical, and chill. But do you know what I think is being cool? It’s being happy. And you seem really happy tonight, Sydney! You know, when somebody criticises you, or says something behind your back – those words that they said about you, it’s like you feel like those words are written all over your face, all over you. And… and then, those words start to become echoes in your own mind. And then, there’s a real risk that those words could become a part of how you see yourself. The moment that you realise that you are not the opinion of somebody who doesn’t know you or care about you – that moment, when you realise that, it’s like you’re clean.”

[callitsnake13]

does taylor notice only those who she follows or....

[allylovestay]

When they don’t calm down and you’re over it

[swiftiesummer-deactivated201911]

When they don’t take several seats and try to restore the peace!

[swiftieemerald]

when you finished drinking beer out of plastic cups

[crimsonredtaylor]

when and man talks shit 

[allylovestay]

when there were five holes in the fence

[likeagold-rush]

watching someone compare are the girls who are killing it like

[iknowineverthinkbeforeijuuummp]

When its 7am!!

[callitsnake13]

But they're comin' at your friends like a missile

[taysdetective]

When they step on your gown

[navyaalovestaylor]

When he calls you up just to break you like a promise

[imonsomenewshit]

When they need to just stop, like can they just not

[swiftieemerald]

when they’re taking shots at you like it’s patrón

[allylovestay]

When they don’t calm down and you’re over it

[swiftiesummer-deactivated201911]

When they don’t take several seats and try to restore the peace!

[swiftieemerald]

when you finished drinking beer out of plastic cups

[crimsonredtaylor]

when and man talks shit 

[allylovestay]

when there were five holes in the fence

[likeagold-rush]

watching someone compare are the girls who are killing it like

[iknowineverthinkbeforeijuuummp]

When its 7am!!

[callitsnake13]

But they're comin' at your friends like a missile

[littleoblivions]

i haATE HER WHAT’S IT CALLED

[taylorswift]

SOON MY LOVE SOOOOOOON

[callitsnake13]

TAYLOR WHAT'S YOUR NEW CAT'S NAME

[taylorswift]

ME! Out now! Made this song with Brendon Urie and Joel Little. Dave Meyers and I co-directed the video. And everyone knows you can’t spell awesome without DAVIDBRENDONJOEL. Oh wait… taylorswift.lnk.to/meTU

[callitsnake13]

TAYLOR ADOPTED ANOTHER CAT

[islandbreeze-13]

I hate her

[another-like-me]

SHE DID NOT

[claudiaheartstay]

TAYLOR YOU DIDN’T-

[taylorswift]

I truly didn’t. I know how sensitive that topic is in these parts.

[callitsnake13]

I HATE YOU TAYLOR OMGJSKSKSKS

[heavenlybrendon]

Brendon talking about Taylor Swift’s countdown (April 24th, 2019)

[newromanticsinwonderland]

GIVE THE MAN AN OSCAR!

[taylorswift]

This was some of the most impressive acting I have EVER seen.

[callitsnake13]

OH MY GOD TAYLOR!!!!!!!!!!

[taylorswift]

So… Kelsey Montague helped me pull off the best surprise clue reveal today in Nashville!! Thank you to everyone who showed up, I’ve never been more proud of your FBI level detective skills. Next clue: I’ll be joining the magnificent Robin Roberts for a chat tonight on ABC live from Nashville 💕💕💕💕💕💕💕

[callitsnake13]

MOM I LOVE YOU SO SO MUCH