Friday, February 13, 2015

Excerpts from the Clown's Laptop Files

This being the journal of Doctor Mock, beginning 7 June, 2001. I call myself Mock here, but they will insist on calling me the Clown. No matter. The marks of the old world must be covered. We are human here, after a fashion. Oh dear, I have rambled on a bit, haven't I? This Nightmare Pixie creature we encountered amidst the chaos of this world's preliminary upheaval fascinates me. She claims to be a native, not a creature of the old world like us. It is true that she does not bear the brand of the Court. And yet… Enough. This device tires me.

14 September 2001
Dendritic cells (DCs) are sentinel cells of the immune system and are essential for inducing a proper immune response. The mechanisms driving the development of DCs are not fully understood. Although the roles of cytokines and transcription factors have been a major focus, there is now substantial interest in the role of microRNAs (miRNAs). miRNAs are small RNAs that regulate gene expression by targeting messenger RNAs for translational repression and ultimately degradation. By means of deep sequencing, we have assembled a comprehensive and quantitative resource of miRNA expression during DC development. We show that mature DCs and their hematopoietic progenitors can be distinguished based on miRNA expression profiles. On the other hand, we show that functionally distinct conventional and plasmacytoid DC subsets are indistinguishable based on miRNA profile. In addition, we identify differences between ex vivo purified conventional DCs and their in vitro Flt3L-generated counterparts. This miRNA expression atlas will provide a valuable resource for the study of miRNAs in DC development and function.

5 January 2002
They have me doing all the interrogation work for this facility, now. It's interesting work, but somewhat of a distraction. Still, they have provided me with the best laboratory I'm likely to find for a while, and given me a fair amount of latitude regarding the disposition of post-interrogation materials. Sarana and Erith are excelling at their considerably more aggressive roles. I find this "Unbeholden" alliance to be a rather interesting anomaly for this region. Some of their enemies are quite committed, despite the inevitable collapse of the structures they adhere to. What interests me more, however, is when information about the Unbeholden comes to me from captives, information which has not reached me from my allies. I suspect that the Unbeholden's inner circle is considerably more ambitious than the Nightmare Pixie would have me believe. Or maybe she doesn't know, either.

25 April 2004
I'm in them: every sprouting tree, every child of peace, every cloud and sea. You see with your eyes. You see destruction and demise, corruption in the skies from this fucking enterprise. Now I'm sucked into your lies through Russell – not his muscles, but percussion he provides for me as your guide. Y'all can see me now 'cause you don't see with your eyes. You perceive with your mind. That's the inner. So I'mma stick around with Russ and be a mentor – bust a few rhymes so motherfuckers remember what the thought is. I brought all this so you can survive when law is lawless, feeling sensations that you thought were dead. No squealing! Remember that it's all in your head.

26 December 2005
Darling Sarana has murdered another of these primitive settlements. Her brother insists on taking the blame, but it would be ludicrous to believe that he committed such a precise series of executions. I must admire her artistry – the villagers almost appear to have been struck down by a poison gas that magically opened their veins all at once – but it seems wasteful. I explained to the Pixie that they are only children and that I will remind them of the need for self-discipline. She seemed unconcerned, however, even pointing out that these creatures are prolific breeders, so there will always be more to collect for the work.

32 January 2006
Advancements in genome editing have relied on technologies to specifically damage DNA which, in turn, stimulates DNA repair including homologous recombination (HR). As off-target concerns complicate the therapeutic translation of site-specific DNA endonucleases, an alternative strategy to stimulate gene editing based on fragile DNA was investigated. To do this, an episomal gene-editing reporter was generated by a disruptive insertion of the adeno-associated virus (AAV) inverted terminal repeat (ITR) into the egfp gene. Compared with a non-structured DNA control sequence, the ITR induced DNA damage as evidenced by increased gamma-H2AX and Mre11 foci formation. As local DNA damage stimulates HR, ITR-mediated gene editing was investigated using DNA oligonucleotides as repair substrates. The AAV ITR stimulated gene editing >1000-fold in a replication-independent manner and was not biased by the polarity of the repair oligonucleotide. Analysis of additional human DNA sequences demonstrated stimulation of gene editing to varying degrees. In particular, inverted yet not direct, Alu repeats induced gene editing, suggesting a role for DNA structure in the repair event. Collectively, the results demonstrate that inverted DNA repeats stimulate gene editing via double-strand break repair in an episomal context and allude to efficient gene editing of the human chromosome using fragile DNA sequences.

15 August 2006
The Nightmare Pixie exists in a semi-transcendent state, much like we would, if not bound by the Court's censure. I suspect that, like us, she is immortal, but cannot be sure. Her easy, natural size-changing is not a physical transformation, but an uncanny distortion of space itself. The manner in which this is accomplished is still beyond me. The Caterpillar is silent on the matter. As to the Pixie's other powers, I am, of course, no stranger to necromancy, but I would be interested to learn where she studied it. Once, she took particular care to wipe out all signs of a raid by creatures that claimed to be from a place called "Dimension Q." Could this be a clue to her own origins? Once I've finished vivisecting this Hero Corps agent, I shall look further into the matter. I find it exceedingly irritating that the animal keeps losing consciousness. Stimulants are difficult to requisition here.

14 November 2009
My hydraulic reanimation experiments proceed apace. Today I finally solved a problem that has been plaguing me for some time: odor. Zombies don't smell good, and they leave chunks behind that smell just as bad. It doesn't help that all the mechanical equipment I've installed generates heat. My first thought was to install those plug in air freshener things on their backs. It was quickly determined that the smell of rotting flesh and jasmine is not much better than the smell of rotting flesh. Next I tried sewing quicklime pockets all over their uniforms. Lime worked in the old days, right? This led to some problems though. For instance, although the electronic systems in my hydraulic zombies are not waterproof and the creatures have been programmed to avoid the stuff, some of them still seem drawn to the swimming pool. It was a particularly bad day when I lost two mine sweeper zombies and a carrier to the pool, and then one of our (living) patriot soldiers emerged with second degree burns all over his body. It seems that lime is rather caustic when mixed with water. Who knew?
     Finally, I got my hands on a unique vinyl based embalming fluid. They say it's the same stuff used by the creators of Val Kilmer. After some tinkering with the formula (I don't know what Barker has been saying, but he volunteered and I'm not the one who "melted" his ear) I managed to adapt it to my needs. Now I just drop my new acquisitions in the tub and let them soak. A few hours later, I have a corpse with clean, odor locked flesh and a dense, rubbery consistency. The pool is still a problem, though.

12 January 2009
I have obtained the body of George Reeves and he is soaking in Kilmer fluid while I work on the structural supports necessary to animate his highly decomposed flesh. The kids have made several trips to Beta City for one of my other projects. Am looking forward to reviewing their findings.

14 January 2009
Had lunch with the receptionist today and slipped some blowfish toxin into her drink. This led me to consider some interesting possibilities. My approach has always been to use a standard electronic CPU in controlling the reanimated. Attempts to stimulate necrotic brain tissue have so far been disappointing, so I usually just scrape all that stuff out and feed it to the mutts. While this is fine if all we need is traditional zombie work, it does not bring back any of the original personality, so I have to just make that part up.
    So I started thinking - maybe I can encode a few necromantic incantations onto a silicon chip - maybe something that would enable the CPU to get in touch with the appropriate soul. It would still be a scientific reanimation; there would just be that one download from the netherworld to bring back some personality. Reeves needs a lot of work, but my assistants can handle the cosmetic stuff. I, on the other hand, have a big stack of unhallowed texts from the office library and a dead receptionist to experiment with!

07 March 2009
I disagree with the plan to establish a foothold by way of Lightfoot Island and Tripod City. The organized crime presence that is already prevalent in those locations will be far more trouble for Unbeholden enterprises than the over-confident government of Beta City, thinking that they're safe behind their wall of slightly enhanced primates. Perhaps the Pixie will listen to me. I tried at some length to explain my position to one of Plague Dog's mutts, but the creature was panting and watching a nearby squirrel through almost the entire conversation. One is led to suspect that a certain amount of replicative fading is involved.

24 June 2009
By the teeth of Ravana! That was NOT George Reeves! Surely, though, with all those rhinestones, the creature will be easy to find and re-capture.

17 April 2011
Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. Note to self: request more pre-sliced sandwich cheese.

18 April 2011
Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 μmol/L) or its analogue berberine (1 μmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting. This cheese is terrible. Make a note to requisition that supply clerk for experimentation.

27 April 2011
In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation, and the clerk's screams were most satisfying. In the serum-starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serum-starved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells. After careful review of these findings, I can only conclude that Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b.

17 December 2014
I was able to get a number of surreptitious scans of our "Azrak" friends, and have noticed several possible similarities to the Ilkani technology present in the Twice Born. Could Covenant be playing us for fools? No deception would surprise me from Covenant. I can read nothing from him, and that disturbs me.

05 January 2015
Increasing evidence suggests that proteins exhibiting “prion-like” behavior cause distinct neurodegenerative diseases, including inherited, sporadic and acquired types. The conversion of cellular prion protein (PrPC) to its infectious protease resistant counterpart (PrPRes) is the essential feature of prion diseases. However, PrPC also performs important functions in transmembrane signaling, especially in neurodegenerative processes. Beta-amyloid (Aβ) synaptotoxicity and cognitive dysfunction in mouse models of Alzheimer disease are mediated by a PrPC-dependent pathway. Here we review how this pathway converges with proinflammatory cytokine signaling to activate membrane NADPH oxidase (NOX) and generate reactive oxygen species (ROS) leading to dynamic remodeling of the actin cytoskeleton. The NOX signaling pathway may also be integrated with those of other transmembrane receptors clustered in PrPC-enriched membrane domains. Such a signal convergence along the PrPC-NOX axis could explain the relevance of PrPC in a broad spectrum of neurodegenerative disorders, including neuroinflammatory-mediated alterations in synaptic function following traumatic brain injury. PrPC overexpression alone activates NOX and generates a local increase in ROS that initiates cofilin activation and formation of cofilin-saturated actin bundles (rods). Rods sequester cofilin from synaptic regions where it is required for plasticity associated with learning and memory. Rods can also interrupt vesicular transport by occluding the neurite within which they form. Through either or both mechanisms, rods may directly mediate the synaptic dysfunction that accompanies various neurodegenerative disorders.

13 January 2015
By happy chance – some sort of scuffle on the lake – a specimen of the Azrak soldiers has finally come to me! They are not Ilkani, although I see tantalizing similarities in their technology. I find radiation signatures that suggest potential chronal displacement, although this could just as easily have resulted from extended hyperspace exposure. The level of symbiosis present in their cybernetic attachments is impressive, although I suspect that the tools they use naturally would be quite dangerous to the local life forms. I shall have to send the children out to gather material.

27 January 2015
The Azrak, it seems, have discovered quite an elegant solution to the problem of army-building. The soldier and the weapon are one and the same. What I thought was a controlling operator was simply a host, no more than a disposable biological matrix. Any material would do. I suspect that, in no time at all, the creature to which I have attached this set of armaments will be indistinguishable from the Azrak from which I removed them. This being the case, it seems we have very little information on the true appearance of the original Azrak, assuming such a creature even exists.

5 February 2015
It's amazing what these primates will carry into their secure facilities when it looks like one of their own.

No comments:

Post a Comment