#E3 exhibit

[nonfeelings]

Playstation exhibit by Mauk Design

[lunarriviera]

[overthinking about blorbo follows] [quasi-spoiler for uts s2 e3] look okay so here's the thing. shen yi is an insanely gifted classically trained painter who now lbr spends most of his working life sketching holdup mugshots off of grainy cctv footage, an occupation that at this point for him has to be boringly straightforward. maybe once in a while there's a cool serial murderer and he gets to come up with a way to reconstruct an entire person's body from one molar, or invent some new shrimp colors or something. then he goes home and paints his fucking heart out all night and for what, who is seeing it? who is seeing him? (and don't say du cheng bc i love him but we all know he probably wears black because he's red-green color blind.) so here he is, showing his canvases in a little group exhibition and trolling quietly amongst the clueless spectators, and no one even knows who he is because he's not showing up at the gallery opening in a suit du qing poured him into, clutching a glass of room-temperature champagne. instead here's someone standing the correct distance away from the canvas and you can practically hear shen yi's invisible antennae go sproing. idek who this charismatic pointy-faced guy is yet, maybe he's under the skin's answer to sheev palpatine but the point is, no one who can see what shen yi is doing talks to him about his work. so when weasel man says "he's a genius" and shen yi gives that tiny smile that's so frail it's almost invisible— he gave that smile one time before in s1, remember? when du cheng says "it could be that shen yi is wrong—but that's impossible, so we're crossing that one out." it's a beautiful little character note from tan jianci bc very likely shen yi isn't even aware he's doing it. maybe he's even telling himself "oh please how dare this guy, who does he think he is, clement greenberg"—shen yi who literally set fire to his ambition in the service of honing a moral compass so ruthless and unbending you could set greenwich mean time by it. but somewhere down in there, always—inside any person who chooses a life devoted to making things—is the desire for those made things to be seen.

who was the last person who said "he's a genius" not about his police work but about his painting? the last person who looked carefully at all of his values, hues, lines, shapes, gestural movements, mark-making, brushstrokes, depth of field, play of light, and really saw what he was doing, enough to be critical of it? when you're a working artist and someone sees you well enough to critique you intelligently? the pleasure is breathtaking, frankly on a spectrum with the erotic. (you could also argue he's smiling ruefully at the declaration that the painter's having become a cop is what ruined his work; when shen yi possibly thinks: you know nothing, it opened up everything for me. but i'm not so sure about that. because did it? has it? do we know that?) tl;dr weasel man is holding out an opened box of fresh turkish delight and it remains to be seen whether shen yi is going to faceplant into it. but i for one could not blame him. it is exhausting to have an enormous part of your psyche be all but completely invisible for years on end.

[hatosaur]

I just wanted to hear your opinion on the way the tlou fandom portrays Ellie, I have a feeling like everyone mischaracterises her (especially on tumbrl and tik tok) and makes her some kind of a fuckboy (literally Dina and Cat had to make first moves cuz she was nervous)

oh yeah they do, and i think it's kinda of a projection of how they find her hot because of her being aggressive and kill-hungry in tlou2. aggression/female rage + masc lesbian = hawt, is the logic, and i kinda get it. i can't lie, i've written her with the same motivation sometimes because it's a power fantasy.

but still it feels disingenuous to her character to just portray her as an emotionless fuckboi because it's purely based on that character arc. she's attractive, masculine, and can exhibit "alpha" behavior (weed den), sure, but she's also shy, introverted, and soft-spoken. she writes poetry and songs and frets over her crushes! i like when ellie's soft side is shown alongside her more survivalist side because it's what makes her character interesting; that she can be the type to averting her eyes from her gf shyly and moments later, focus in on bodying infected and stealthing around. that balance is where the intrigue lies.

like that one e3 teaser exemplifies this so well! ellie doubting that dina could ever like her and stating that she's not a threat to anyone else who wants her, she gets kissed, and it transitions into how dangerous of a person she is, then back again to her smiling over dina's feelings being mutual.

not only this but the games are 100% deadset on showing you how vulnerable she can be despite her rough side. like she's not an impenetrable force, she's a 19 y/o girl who just lost her dad-figure and spirals because of the mistakes she made.

to me, THAT'S ellie and THAT'S what makes her cool and interesting, not one side of her or the other.

[compneuropapers]

Interesting Papers for Week 8, 2024

Sensory prediction error drives subconscious motor learning outside of the laboratory. Albert, S. T., Blaum, E. C., & Blustein, D. H. (2023). Journal of Neurophysiology, 130(2), 427–435.

Working memory load impairs transfer learning in human adults. Balter, L. J. T., & Raymond, J. E. (2023). Psychological Research, 87(7), 2138–2145.

Objects sharpen visual scene representations: evidence from MEG decoding. Brandman, T., & Peelen, M. V. (2023). Cerebral Cortex, 33(16), 9524–9531.

Specific patterns of neural activity in the hippocampus after massed or distributed spatial training. Centofante, E., Fralleoni, L., Lupascu, C. A., Migliore, M., Rinaldi, A., & Mele, A. (2023). Scientific Reports, 13, 13357.

Hormonal coordination of motor output and internal prediction of sensory consequences in an electric fish. Fukutomi, M., & Carlson, B. A. (2023). Current Biology, 33(16), 3350-3359.e4.

Subcortico-amygdala pathway processes innate and learned threats. Khalil, V., Faress, I., Mermet-Joret, N., Kerwin, P., Yonehara, K., & Nabavi, S. (2023). eLife, 12, e85459.

Neural mechanisms underlying uninstructed orofacial movements during reward-based learning behaviors. Li, W.-R., Nakano, T., Mizutani, K., Matsubara, T., Kawatani, M., Mukai, Y., … Yamashita, T. (2023). Current Biology, 33(16), 3436-3451.e7.

Monkeys exhibit human-like gaze biases in economic decisions. Lupkin, S. M., & McGinty, V. B. (2023). eLife, 12, e78205.

Widespread coding of navigational variables in prefrontal cortex. Maisson, D. J.-N., Cervera, R. L., Voloh, B., Conover, I., Zambre, M., Zimmermann, J., & Hayden, B. Y. (2023). Current Biology, 33(16), 3478-3488.e3.

Synaptic variance and action potential firing of cerebellar output neurons during motor learning in larval zebrafish. Najac, M., McLean, D. L., & Raman, I. M. (2023). Current Biology, 33(16), 3299-3311.e3.

Novelty and uncertainty differentially drive exploration across development. Nussenbaum, K., Martin, R. E., Maulhardt, S., Yang, Y. (Jen), Bizzell-Hatcher, G., Bhatt, N. S., … Hartley, C. A. (2023). eLife, 12, e84260.

Ants combine object affordance with latent learning to make efficient foraging decisions. Poissonnier, L.-A., Hartmann, Y., & Czaczkes, T. J. (2023). Proceedings of the National Academy of Sciences, 120(35), e2302654120.

VIP interneurons in sensory cortex encode sensory and action signals but not direct reward signals. Ramamurthy, D. L., Chen, A., Zhou, J., Park, C., Huang, P. C., Bharghavan, P., … Feldman, D. E. (2023). Current Biology, 33(16), 3398-3408.e7.

A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics. Rodrigues, Y. E., Tigaret, C. M., Marie, H., O’Donnell, C., & Veltz, R. (2023). eLife, 12, e80152.

Sequence anticipation and spike-timing-dependent plasticity emerge from a predictive learning rule. Saponati, M., & Vinck, M. (2023). Nature Communications, 14, 4985.

Statistical inference on representational geometries. Schütt, H. H., Kipnis, A. D., Diedrichsen, J., & Kriegeskorte, N. (2023). eLife, 12, e82566.

High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells. Spirou, G. A., Kersting, M., Carr, S., Razzaq, B., Yamamoto Alves Pinto, C., Dawson, M., … Manis, P. B. (2023). eLife, 12, e83393.

Using occipital ⍺-bursts to modulate behavior in real-time. Vigué-Guix, I., & Soto-Faraco, S. (2023). Cerebral Cortex, 33(16), 9465–9477.

Octave illusion: stimulation frequencies can modulate perception. Whittom, A., Couture, F., Chauvette, L., & Sharp, A. (2023). Psychological Research, 87(7), 2183–2191.

Completeness out of incompleteness: Inferences from regularities in imperfect information ensembles. Zhu, J., Xu, H., Shi, B., Lu, Y., Chen, H., Shen, M., & Zhou, J. (2023). Journal of Experimental Psychology: Human Perception and Performance, 49(9), 1203–1220.

[elle-p]

No, it doesn't say Harf in the final version.

[m1m05a]

根本敬 presents 蛭子能収「最後の展覧会」 - 今後の展覧会 | AKIO NAGASAWA

"蛭⼦能収といえば、世間⼀般の認識としてはテレビタレントにいたおかしな⼈ですが、私にとっては前衛的な漫画やイラストを描く「ガロ」の実に偉⼤な先輩です。

その蛭⼦さんが2014年に認知症の初期段階とTV番組の企画で診断され��した。たしかにその頃から物忘れは著しく、画⼒も微妙な感じになってきてはいました。従来の⼿抜きとは違い、線が思わぬ⽅向へ変化しているのです。

その頃⾃⾝の描いたイラストを指して「⼩学⽣みたいな絵やね」と⾃嘲する様に⾔いました。

しかし、蛭⼦さんと私が師とあおぐ湯村輝彦（aka テリージョンソン）さんが「⼩学⽣みたいに⾒えても絶対におじさんにしか描けない絵」と前向きに評したのでした。

6年後の2020年、皆さんもご存じの通り蛭⼦さんは「レビー⼩体型認知症とアルツハイマー型認知症の合併症」である旨を公表しました。

その際に放った「（これからは）認知症のオレを笑って下さい」という⾔葉に偽りはなく、オレは今まで通りバリバリ仕事をするからこれからも宜しく頼みますという意思表明だったと思います。

しかし、現実はそうは⾏かず、認知症を公表したタレントの仕事はみるみる減り、漫画家としての描いたり、もしくは書いたりといった仕事も激減し今や限りなくゼロに等しいのです。

このまま蛭⼦さんをフェイドアウトさせてはならない、絵を描くことからスタートした蛭⼦さんを最後は絵＝芸術家として飾って貰えたらと考える⼈達が少なからずいて、この度の展覧会は企画されました。

約1年と少し前の話です。

そして準備も整い今年の春から絵を描き出しました。

とはいえ、この展覧会へ向けてキャンバスに向かう頃には症状は進み、かつて⾃らの⼝から出た「⼩学⽣みたいな絵」は「幼児みたいな絵」になっていました。

しかし、件（くだん）の湯村さんの⾔葉に倣えば「幼児みたいに⾒えても絶対におじさんにしか描けない」、より具体的⾔えば「幼児みたいな絵に⾒えても75歳、認知症の蛭⼦能収にしか描けない絵」なのです。

どの絵も「⽣きる」ということが本質的に内包する儚さを突きつけてくるのですが、それでいて幸せな気持ちにもなってしまうのは企画した私達だけでしょうか。

− 根本 敬（特殊漫画家）"

https://www.akionagasawa.com/jp/exhibition/the-last-exhibition/#:~:text=%E8%9B%AD%E2%BC%A6%E8%83%BD%E5%8F%8E%E3%81%A8%E3%81%84%E3%81%88%E3%81%B0,%E6%A0%B9%E6%9C%AC%E2%80%80%E6%95%AC%EF%BC%88%E7%89%B9%E6%AE%8A%E6%BC%AB%E7%94%BB%E5%AE%B6%EF%BC%89

https://www.akionagasawa.com/jp/exhibition/the-last-exhibition/#:~:text=%E8%9B%AD%E2%BC%A6%E8%83%BD%E5%8F%8E%E3%81%A8%E3%81%84%E3%81%88%E3%81%B0,%E6%A0%B9%E6%9C%AC%E2%80%80%E6%95%AC%EF%BC%88%E7%89%B9%E6%AE%8A%E6%BC%AB%E7%94%BB%E5%AE%B6%EF%BC%89

[night-at-the-musian]

looking at the natm tag on pixiv fills my heart with joy. we’re kindred spirits in foaming at the mouth for these exhibits and their guard. our brethren in wanting jedtavius to smooch. to the pixiv-exclusive artists and writers: i love you

go check it out: https://www.pixiv.net/en/tags/%E3%83%8A%E3%82%A4%E3%83%88%E3%83%9F%E3%83%A5%E3%83%BC%E3%82%B8%E3%82%A2%E3%83%A0

[authortobenamedlater]

Predictions, questions, good/bad/neutral about E3.

Why does this show make me so long-winded.

Predictions:

As I already mentioned, Jacob Keyes is not going to survive Reach. I don’t want this to happen, because death seems like too easy an out for him and the Spartans need their Dadmiral, but it’s close enough to canon. He can live on in my AUs.

Kai leads the Spartan-IIIs on Reach. In a couple of trailers we see her in a drop ship with what I’m now certain are SPI helmets behind her. Then she goes to Onyx and steps into the Kurt role. Or maybe she takes over for him. It’s probably too much to hope that we might see them working together. I’ll save that for headcanons and fanfic.

…Does this mean Kai will go out like Kurt at some point? Getting ahead of things.

Miranda is on Onyx doing artifact research and/or working on the science side of the S-IIIs. She did finally show up for two seconds in the “this season on” trailer.

The Covenant forces Cortana to reveal the location of Earth, which is why John is standing on a drop ship with Jupiter in the foreground in one of the trailers.

We will meet Noble Team in some form, especially if Kai is leading the S-IIIs into battle.

Reach is going down. There. At least one of these predictions is guaranteed.

Questions:

WHO is that S-III who looks an awful lot like Corporal Perez? Just a coincidental lookalike? If not Talia, maybe Kat or Lucy? I would love to see Tom and Lucy on screen.

Silver Team is, officially or otherwise, getting separated. Kai and Riz are both justifiably POed at John and Vannak isn’t too happy either, I imagine. Kai got pulled to the S-IIIs and Riz is wondering about “life without all this Spartan $#*!.” Are we going to see John as the one-man army we get in every Halo game except 5, and Silver will become recurring characters? Or, are we making room for John to get a new team? Maybe a team we know already? Like…Blue Team?

I am very curious what the Spartan-IIIs look like in this world. I get the impression they haven’t been around that long, but most of this is fan brain conjecture from trailers. Exhibit A: In one trailer Kai steps out in front of a formation of IIIs and we hear Ackerson saying “make them Spartans.” The IIIs already ARE Spartans. They’ve been around for 20 years by this point.

UNLESS. They’ve basically made the IIIs into the IVs. That could explain a Talia sighting and why Kai is getting tapped to train them. Maybe Reach is their first deployment.

If these are the IIIs who are more like IVs, maybe the Talia Perez lookalike is Sarah Palmer? I hope not, because Frankie Adams of The Expanse fame is live action Palmer in my mind’s eye and I want to keep that illusion as long as possible.

The suits look pretty similar.

Once again getting WAY ahead of myself.

How are they going to resolve the Cortana situation? In one trailer it looks like a Sangheili is putting her on a chip or disk of some kind. Is she going back in John’s head at some point? Who’s going to do this? If she stays on a chip do they have to retrofit his helmet and every other piece of UNSC tech?

Who’s this Var ‘Gatanai Talia names in the last scene? Did the show make an entirely new Arbiter? Is Var going to die and make room for Thel? Is Thel still leading the fleet and Var is on the ground? Does Thel not exist here? Last time we saw Makee she was about to touch the larger artifact. Did she ever touch it?What happened? Are we going to see her during the battle? Will she die again? Will she stay dead?

Good, bad, general commentary:

You all know what I want. I’m here for The Chief and Cortana Show. I want my Chief and Cortana Show. This is not the Chief and Cortana show. I want them back together.

I like how the show is giving us a peek into how the UNSC / ONI bureaucracy and agenda is as big an adversary as the Covenant. A good example of the show telling stories the games can’t. Not that shooting your way through ONI red tape wouldn’t be kind of a hilarious video game.

I currently don’t like how they just wiped Madrigal out of the picture, but I am reserving judgment for now to see how this plays out.

I love Ackerson. I hate Ackerson.

Kind of mad Cobalt Team turned up dead. They deserved better.

I still live in hope of one day meeting Avery Johnson.

Ackerson talks about John “interact[ing] with the Covenant agent” and says he read the report. So all that is common knowledge? And John is just walking around like nothing happened? Weird.

Laera being a boss lady and mama bear is awesome. She is truly the only woman for Soren.

I am SCREAMING and FLAILING and GEEKING OUT over the overt Christian references this season. Making me want to write my “what if a Spartan got religion” story. Gahhhhhh

[lunawings]

Where is Rainbow Live exhibition? And how long it wilk be? I'm asking because i'm going to Japan this summer.

It was in Yurakacho Marui, but unfortunately it only ran from March 1st to March 17th. Sorry about that.

I have a very relevant post of mine you might wanna read, ahah...

But to summarize, basically little event collabs and cafes and shops like this pop up all the time, and unfortunately, they come and go so quickly it's impossible to plan a trip around them.

But, I found this website super helpful: collabo-cafe.com

You might have to search in Japanese to make sure you're finding everything, but it lists all sorts of these little events as they are announced. If anything Pretty Rhythm-related comes up, it should be added to the page below (I searched for プリティーリズム).

https://collabo-cafe.com/?s=%E3%83%97%E3%83%AA%E3%83%86%E3%82%A3%E3%83%BC%E3%83%AA%E3%82%BA%E3%83%A0

This kinda stuff isn't going to be announced until a month or two before so keep checking. Good luck!

[jumpstartfactoftheday]

Over the years, multiple Frankie costumes have been created for official use. The costume in the top left was used for E3, an annual video game exhibition. The costume in the top right was used for meet-and-greet events, such as congratulating JumpStart contest winners. The costume at the bottom was used for music videos featured in JumpStart Sing-Along Time.

[anjalisinghmarketing]

Welcome E3 Group at Matecia 2025 Bangalore | Largest Interior & Exterior Exhibition

Save the date!! 21 Feb - 23 Feb, join E3 Group at Matecia 2025 Bangalore for a grand showcase of exciting interior and exterior surface products!

Experience the future of design with our Boilo Guard, HDMR, XDF, MDF, Pre-Lam, Edge Bands, and Clads.

Don’t miss out on the latest trends and game-changing style! See you there!

Watch More: https://www.youtube.com/shorts/msQFHKjhwqM

[kkumarsblog]

CELMoDs: A Next-Generation Approach in Multiple Myeloma Treatment

The landscape of multiple myeloma treatment is rapidly evolving, with CELMoDs (Cereblon E3 Ligase Modulators) emerging as a promising next-generation therapy. While Revlimid has long been a cornerstone in managing multiple myeloma, challenges such as drug resistance and adverse effects have driven the need for innovative alternatives. CELMoDs offer a compelling solution by providing enhanced efficacy and improved safety profiles.

These novel drugs function by modulating the cereblon protein, leading to the degradation of key proteins essential for tumor cell survival. While their mechanism is similar to immunomodulatory drugs (IMiDs) like Revlimid, CELMoDs exhibit greater potency and selectivity, positioning them as a breakthrough treatment option.

The multiple myeloma treatment market stands to gain significantly from CELMoDs, as they introduce a novel approach to combating this complex and often relapsing disease. Clinical trials have demonstrated that CELMoDs, particularly in combination therapies, outperform traditional treatments in efficacy. As resistance to established therapies like Revlimid continues to grow, CELMoDs are shaping up to be key players in the multiple myeloma drug market.

Beyond efficacy, CELMoDs are designed to improve safety profiles, minimizing side effects that often hinder current therapies. With the multiple myeloma treatment landscape expanding, these next-generation drugs have the potential to improve patient outcomes, extend survival rates, and offer new hope to those with limited treatment options.

As advancements in multiple myeloma treatment continue, CELMoDs are paving the way for a new era of therapeutic innovation. Their potential to succeed Revlimid and redefine treatment standards highlights their importance in the future of multiple myeloma care.

Top Reports Offered By Delveinsight

radicava mechanism of action | how many people have cidp | therapy light benefits | internet of things in medical | health monitoring apps | cardiac monitoring devices | immunomodulatory drugs | izervay reviews | adenovirus stages | what is hemoglobinuria | peripheral artery disease prevalence | arteriotomy | orthopedic implant companies | ropressa | oceanic af | cervical dysplasia stages | tev-48574 | welireg fda approval | nevro hfx programs | axillary hidrosis | lentiginous definition | voquezna gerd | visiox pharma | fluid management systems | cln1 disease | can achondroplasia be treated 

About DelveInsight

DelveInsight is a premier market research and consulting firm specializing in life sciences and healthcare. We provide in-depth insights to help pharmaceutical, biotechnology, and medical device companies navigate a dynamic and competitive industry

Contact Information

Kanishk

kkumar@delveinsight.com

[videoddd]

E3’s Organizers Are Back With a New Event. This Time, Doctors Are Invited Too

The organizers The E3 Games Extravagant Conference announced the event of a dead in 2023. The attendance of the pompous, saturated news of the exhibition was in decline in 2019, and after the COVID-19 LockDown organizers of the Association of Software for Entertainment conducted another virtual one. Show in 2021 before drinking a plug. Now ESA is ready to move on with a new, vaguely described…

[blueoaknx]

Mitochondrial Dysfunction in the Pathogenesis of Parkinson’s Disease

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily affecting motor function due to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The pathogenesis of PD is multifactorial, with emerging evidence pointing to mitochondrial dysfunction as a pivotal event in the onset and progression of the disease. This article provides a comprehensive technical analysis of the role of mitochondrial dysfunction in PD, focusing on key molecular mechanisms, genetic factors, and potential therapeutic strategies.

Mitochondria and Their Cellular Roles

Mitochondria are essential organelles that generate the majority of the cell's ATP via oxidative phosphorylation in the electron transport chain (ETC). In addition to their role in energy production, mitochondria are involved in maintaining cellular homeostasis by regulating calcium signaling, apoptosis, and reactive oxygen species (ROS) production. The proper functioning of mitochondria is crucial for neurons, particularly dopaminergic neurons, which have a high metabolic demand.

Mitochondrial Dysfunction and Parkinson's Disease Pathogenesis

Mitochondrial dysfunction in PD primarily manifests through alterations in mitochondrial bioenergetics, increased oxidative stress, defective mitophagy, and calcium dysregulation. These abnormalities converge on exacerbating neuronal injury, particularly in dopaminergic neurons.

1. Impaired Mitochondrial Complex I Activity

One of the hallmark features of mitochondrial dysfunction in PD is the impairment of mitochondrial complex I, the first enzyme complex in the ETC. Complex I is responsible for transferring electrons from NADH to ubiquinone, a critical step in ATP synthesis. Studies consistently show that PD patients exhibit significant reductions in complex I activity in the substantia nigra, which leads to defective ATP production. This mitochondrial dysfunction results in energy deficits, rendering dopaminergic neurons more susceptible to stressors.

Inhibition of complex I activity is not limited to genetic mutations; environmental toxins such as rotenone and paraquat, which inhibit complex I, have been implicated in Parkinsonian syndromes. Furthermore, complex I dysfunction increases the production of ROS, exacerbating oxidative stress in neurons and contributing to mitochondrial damage.

2. Oxidative Stress and ROS Generation

Mitochondria are both the primary source and target of ROS. The process of oxidative phosphorylation inevitably generates ROS as byproducts, particularly superoxide anion, hydrogen peroxide, and hydroxyl radicals. Under normal conditions, ROS are detoxified by endogenous antioxidant systems. However, in PD, mitochondrial dysfunction leads to an imbalance between ROS production and the cell’s antioxidant defenses.

The substantia nigra, which is particularly vulnerable in PD, is exposed to elevated ROS levels due to the high metabolic rate of dopaminergic neurons and the catabolism of dopamine, which generates additional ROS via the action of monoamine oxidase (MAO). Accumulation of ROS results in lipid peroxidation, protein misfolding, and mitochondrial DNA (mtDNA) mutations, all of which contribute to neuronal death and the progression of Parkinson’s pathology.

3. Mitophagy and Dysfunctional Quality Control Mechanisms

Mitophagy, a selective autophagic process that removes damaged or dysfunctional mitochondria, is crucial for maintaining mitochondrial quality and function. In PD, mitophagy is impaired, leading to the accumulation of damaged mitochondria within neurons. The PINK1-parkin pathway plays a pivotal role in the initiation of mitophagy. PINK1, a mitochondrial kinase, accumulates on depolarized mitochondria and recruits the E3 ubiquitin ligase parkin, which ubiquitinates outer mitochondrial membrane proteins to tag them for autophagic degradation.

Mutations in the PINK1 and parkin genes, which are associated with autosomal recessive forms of PD, disrupt this process and contribute to the accumulation of dysfunctional mitochondria. This failure to remove damaged mitochondria exacerbates oxidative stress and promotes the activation of apoptotic signaling pathways. As mitochondrial dysfunction progresses, neuronal survival becomes increasingly compromised, accelerating disease progression.

4. Calcium Homeostasis and Mitochondrial Regulation

Mitochondria play a critical role in buffering cytosolic calcium levels. Neurons, due to their high metabolic activity, are particularly dependent on mitochondrial calcium buffering to prevent cytotoxic calcium overload. However, in PD, mitochondrial dysfunction leads to impaired calcium handling, resulting in an increase in cytosolic calcium concentrations.

Elevated calcium levels activate a variety of calcium-dependent enzymes, such as calpains and phospholipases, that further damage cellular structures. Additionally, excessive calcium in mitochondria can activate the mitochondrial permeability transition pore (mPTP), leading to mitochondrial depolarization, the release of pro-apoptotic factors such as cytochrome c, and eventual cell death.

Genetic Factors in Mitochondrial Dysfunction in PD

Genetic mutations that directly affect mitochondrial function have been identified in familial forms of PD. These mutations often impair mitochondrial dynamics, quality control, and bioenergetics, contributing to the pathogenesis of the disease.

PINK1 and Parkin Mutations: Mutations in the PINK1 gene and the parkin gene, both involved in the regulation of mitophagy, lead to impaired mitochondrial quality control. PINK1, a serine/threonine kinase, normally accumulates on damaged mitochondria and recruits parkin to initiate mitophagy. Loss of PINK1 or parkin function results in the accumulation of dysfunctional mitochondria, contributing to neuronal degeneration.

LRRK2 Mutations: The LRRK2 gene encodes a large protein kinase involved in multiple cellular processes, including mitochondrial dynamics and autophagy. Mutations in LRRK2 are the most common genetic cause of PD, particularly in late-onset forms. LRRK2 is implicated in the regulation of mitochondrial fission and fusion, processes that control mitochondrial morphology and function. Dysregulation of these processes leads to the fragmentation of mitochondria, impaired mitochondrial function, and increased susceptibility to oxidative stress.

Alpha-Synuclein and Mitochondrial Interaction: Alpha-synuclein, the protein most notably associated with Lewy body formation in PD, has also been shown to interact with mitochondrial membranes. Aggregation of alpha-synuclein disrupts mitochondrial dynamics, leading to decreased mitochondrial respiration and increased ROS production. This interaction exacerbates mitochondrial dysfunction and accelerates neurodegeneration.

Environmental Toxins and Mitochondrial Dysfunction

Environmental exposures, particularly to pesticides like rotenone and paraquat, have been shown to inhibit mitochondrial complex I, leading to oxidative stress and mitochondrial dysfunction. These toxins induce PD-like symptoms in animal models, supporting the hypothesis that environmental factors contribute to the pathogenesis of the disease.

Therapeutic Approaches Targeting Mitochondrial Dysfunction

Given the central role of mitochondrial dysfunction in PD, therapeutic strategies aimed at restoring mitochondrial function are being actively explored. These include:

Antioxidant Therapies: Antioxidants such as coenzyme Q10 (CoQ10) have been proposed to alleviate oxidative stress by scavenging ROS. CoQ10 functions as an electron carrier in the ETC and may help restore mitochondrial bioenergetics in PD. Clinical trials, however, have shown mixed results, necessitating further research.

Gene Therapy: Gene therapy approaches aimed at correcting genetic defects that impair mitochondrial function are under investigation. For example, restoring PINK1 or parkin function in neurons may enhance mitophagy and mitigate mitochondrial damage.

Mitochondrial Replacement Therapy: Mitochondrial replacement or mitochondrial transplantation holds promise as a therapeutic strategy for restoring mitochondrial function in PD. Early-stage studies are exploring the feasibility of mitochondrial transplantation into dopaminergic neurons to restore cellular function.

Exercise and Lifestyle Interventions: Regular physical exercise has been shown to stimulate mitochondrial biogenesis and improve mitochondrial function. Exercise-induced upregulation of mitochondrial regulators such as PGC-1α may provide neuroprotective benefits in PD by enhancing mitochondrial turnover and reducing oxidative damage.

Conclusion

Mitochondrial dysfunction is a central event in the pathogenesis of Parkinson's disease, contributing to the degeneration of dopaminergic neurons through mechanisms such as impaired mitochondrial complex I activity, oxidative stress, defective mitophagy, and disrupted calcium homeostasis. Genetic mutations in key mitochondrial regulators such as PINK1, parkin, and LRRK2 exacerbate these defects, while environmental toxins further contribute to mitochondrial damage. Targeting mitochondrial dysfunction through antioxidant therapies, gene therapy, and lifestyle interventions holds promise for mitigating the progression of Parkinson's disease. Understanding the intricate molecular mechanisms linking mitochondrial dysfunction to neurodegeneration in PD will be crucial for developing effective therapeutic strategies.

[sudheervanguri]

Lupin Ltd, a globally renowned pharmaceutical leader, is seeking skilled professionals for GSCO - Executive and Sr Executive roles at their facility in Nagpur. These roles are tailored for individuals experienced in supply and planning management, product management, and the pharmaceutical manufacturing process, especially in tablets, capsules, and injectables. Job Location and Application Process Location: Lupin Ltd, Nagpur, India Application: Interested candidates can share their resume at amangupta9@lupin.com or saurabhsharma4@lupin.com Position Details and Qualifications Position Levels: Executive (E2) Sr. Executive (E3) Qualifications: B Pharm, M Pharm, or MSc with strong pharmaceutical or OSD/Injectable unit background. Experience Required: 7 to 9 years in supply planning, product management, and production coordination. [caption id="attachment_58299" align="aligncenter" width="930"] Lupin Ltd Job Openings for GSCO - Executive, Sr Executive Roles[/caption] Key Responsibilities 1. Supply and Planning Coordination Collaborate with PDL, R&D, and Quality teams to create an integrated plan for exhibit and pre-validation batches. Work closely with Production for executing planned tasks and providing daily status updates. 2. Inventory and Procurement Management Oversee inventory metrics like R vs. C vs. A (Requirement, Commitment, and Actual) and conduct weekly data reviews with cross-functional teams. Manage procurement plans using SAP and MRP processes. Experience with Kinaxis software is advantageous. 3. Production Data Analysis Monitor inventory levels of raw materials, packaging materials, and finished goods. Excel proficiency is essential for managing data and preparing insightful reports. Have a basic understanding of manufacturing machinery capabilities to optimize production planning. Skills and Competencies Technical Skills: Kinaxis software expertise for efficient demand planning. Proficient in SAP for handling MRP and procurement plans. Advanced skills in Microsoft Excel for inventory and data analysis. Industry Knowledge: Strong understanding of OSD (Oral Solid Dosage) and injectable production processes. Background in handling pharmaceutical supply chain processes with a focus on tablets, capsules, and injectables. Analytical and Communication Skills: Strong analytical skills for managing large databases and problem-solving. Effective communication and interpersonal skills for coordinating with cross-functional teams like procurement, quality assurance, and artwork development.