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Can you write a full process of conversations between ATC and pilots during a flight?
I'll give you the some exchange of conversation with a single transit flight, and to keep it simple I am assuming that it is cleared to enter the airspace, the weather is fair, the flight is operating normally and aircraft has no conflicting traffic on its route:Aircraft calls our Area Control Unit on our frequency 10 minutes prior entring into our airspace to get entry clearance. The call may be as follows: “Lahore Control, Speedbird 256, estimating position SAMAR time 2100. Maintaining flight level 340. 5304 on the squawk. Requesting entry clearance.” Then the controller sees the aircraft's flight plan for its routing and responds with the clearance which may be as follows: “Speedbird 256, Lahore Control, cleared to position PAVLO from SAMAR on route A466 to DI thereafter N644 to PAVLO. Maintain flight level 340. Report position SAMAR.” The pilot is expected to readback the complete clearance correctly and the controller acknowledges if the readback is correct.When aircraft reaches the reporting point, the pilot calls “Speedbird 256 position SAMAR” and the controller acknowledges and may ask it to report at another fix point. The call will be like this: “Speedbird 256, identitied position SAMAR with squawk 5304. Next report position JHANG.” 'Identifying' the aircraft is a message which tells the pilot that they are in radar coverage of the ATC unit. The pilot readbacks again and the controller acknowledges if the readback is correct.If aircraft wishes to climb it will give a call like this: “Speedbird 256 request climb flight level 360.” If level is available then climb is given by the controller: “Speedbird 256 climb flight level 360.” If climb is not available, assuming due to traffic, then the controller replies and gives the reason for the unavailablity: “Speedbird 256, flight level 360 not available due succeeding traffic maintaining 360, 20 miles ahead.”Aircraft may also request frequency for the next ATC unit (if the pilot does not already know it) so that it can get an entry clearance from the next unit, just like it did with with our unit.Upon reaching the TCP, tranfer of control point, we ask the aircraft to changeover to the next FIR's frequncy thereby handing it over to the next unit. The call would be like this: “Speedbird 256, position PAVLO, Lahore radar services terminated, contact Kabul on 128.5.”
How would I make, say, an 8k image texture of wood, concrete, or a leaf? Do you need to do that with a camera, or can you use Photoshop?
An 8K image is nominally 8000 x 4000 = 32 megapixels.Get an 8K CameraSo the straightforward way is to shoot with a camera capable of delivering something on the order of 32 megapixels. Your first hurdle will be the simple fact that most video cameras don’t shoot 8K and most still cameras, even though that shoot in excess of 32 megapixels, don’t do it in 16:9.But let’s look at our tools. We have the Canon EOS 5Ds, which shoots a 50 megapixel shot. That’s 8688 x 5792 pixels, so you can get your cropped 8K video shot. We have the Nikon D850 at 8256 x 5504 pixelsm, which works with a straight crop, or the Sony A7r mark II at 7952 x 5304 pixels, which is probably close enough for any reasonable need (this would be “8K class”, just as UltraHD at 3840 x 2160 isn’t pedantically 4K, but it’s 4K class).Getting a bit cheaper, my Olympus Pen F shoots in a high resolution mode that delivers an 8160 x 6120 effective image, which would allow you cropping. This is done by taking eight shots with single and half-pixel movement of the sensor, and it only works on motionless images with a tripod. The image may not be quite as sharp as that of the EOS 5Ds, but the color is better, since the multi-photo shot takes red, green, and blue samples for every pixel.Make an 8K CompositeHere’s the place that Photoshop may be of some assistance. You may not have access to an 8,000-pixel wide camera, but if you have any old camera, you can make a photo by compositing.The basic idea is to take multiple, overlapping shots of your subject. Again, it’s best to work from a tripod, in a studio setting to control lighting. So with my aforementioned Pen F, I have a single shot resolution of 5200 x 3904. If I take three vertical shots, I can get a decent 8000-something x 5200 image with 30% overlap, which is just dandy.So I’d bring these three shots into Photoshop or Lightroom and do a panoramic merge. That gets me the single large photo that I can now crop to a clean 8000 x 4000, or whatever variation of 8K you’re actually after.Get ArtisticWhat you can’t do in Photoshop is enlarge a lower resolution image. Well, you can, but it’s still going to look like a lower resolution image.If you need a sharp 8K image, you’ll pretty much need to use the camera techniques. But there are other options. If you’re looking for something that’s acceptable as a background or whatever at 8K resolution, you can resize a lower resolution image to 8K, then mess around with art filters in Photoshop. When you apply an effect to a resized image, the effects take place at the increased resolution. You’ll have to mess around with the effects to find something you like, but it works fairly well for many needs.
Why does the house edge get higher in blackjack with more decks?
It’s not a simple effect. Additional decks change the game in a number of small ways, that just happen to work to the disadvantage of the player.One of the larger effects (but still small) is the probability of getting a blackjack. With one deck there are 4 aces, 16 tens and 52 cards. There are [math]4\times16=64[/math] ways to get a blackjack, and [math]\binom{52}{2}=\frac{52\times{51}}{2}=1326[/math] possible starting hands. [math]\frac{64}{1326}=0.04827[/math].With two decks, both numerator terms double. 8 aces and 32 tens give the player [math]8\times{32}=256[/math] ways to get blackjack. But while one term in the denominator (52) doubles to 104, the other term (51) more than doubles to 103. [math]\binom{104}{2}=\frac{104\times{103}}{2}=5356[/math]. That’s more than [math]4\times{1326}=5304[/math]. Therefore the ratio falls, [math]\frac{256}{5356}=0.047800.04827[/math].The difference, [math]0.00047[/math], multiplied by the 1.5 times blackjack pays in good casinos, represents a loss to the player of [math]0.00070[/math], or a reduction of 0.07% in edge. With infinite decks, the chance of a blackjack is [math]2\times\frac{1}{13}\times\frac{4}{13}=\frac{8}{169}=0.04734[/math], so slightly more than half the loss of going to infinite decks occurs when you go from 1 to 2 decks.But lots of other stuff changes as well. The dealer’s chance of a blackjack falls—but since the house doesn’t pay itself 1.5 times for blackjack there is still a net loss to the player.It’s a more complex computation, but if you work through all the numbers the dealer will bust with [math]0.28359[/math] probability using one deck falling to [math]0.28258[/math] with two decks, and [math]0.28182[/math] with infinite decks. There are advantages for the player as well, such as more chance of getting doubles to split with more decks. That helps because the player can sometimes improve her chances by splitting, while the dealer cannot split.The biggest single effect, although it’s complicated to calculate, is that with more decks it’s more common for both the dealer and the player to bust (assuming the dealer deals out his hand either because other players are in the hand, or in the interests of mathematics). The most common reason to bust is to hit and get a 10, with more decks the chance that both players get hit with a 10 is higher, because removing the player’s ten from the deck has less effect on the dealer’s chance of getting a 10. Since the casino wins when both player and dealer bust, and since this happens around 9% of the time, changes to this probability really matter. But not only do you have to compute all the possible card combinations, you have to account for the player’s choices (the dealer’s choices are fixed). This takes a computer, although the math is simple in principle.More decks are not bad for card counters in a direct sense, but they hurt because the house will deal less deeply into the shoe. The house doesn’t like to shuffle too often, because it slows down the game. With 8 decks it could shuffle halfway through, and still shuffle only about a quarter as often as with a single deck. The advantage to counting rises as you get deeper into the deck, and this is especially true for team counting.
What is the one thing you'd like most to change about the world?
If I am allowed to change only one thing.. I will erase the borders between nations. I will eradicate the term called nations and change it into one “World”.Why should Homo sapiens (biological name of human) need to be separated based on place of birth? Let there be only one country in the name of “World”. Let every human in the world receive EQUAL amount of good and adequate food, health and wealth.A child should not suffer because he/she was born in Somalia rather than USA. Also.. the one world concept will abolish the reason for war and military funds which can be used to protect this World’s environment. Let all the cultures and languages be celebrated. There should not be domination by anybody upon anybody.There should not be competition to become super power. Trump and Putin will become brothers. There should not be a term called discrimination. There should not be difference between Brahmin and Dalit, White and Black, Shiya and Sunni. Only peace and happiness. It literally means.. there is nothing called “my country” “my people”.. But every fellow human is my family.Well.. hundreds of years ago.. A Tamil poet called Kaniyan poongundranar told “yaadhum oore yaavarum kelir”. :)
Why is it so hard to develop RAS inhibitors?
What is Ras?Ras is any protein part of the Ras superfamily of proteins related in structure. Ras is a ubiquitous protein expressed in all cells in our body.  Ras proteins are part of a group of proteins termed the small GTPase class. Ras proteins are general involved in cell growth, differentiation, and survival. As you can see this makes the Ras superfamily of proteins the perfect candidate for contributing to cancer growth (unregulated proliferation and growth of cells). Ras specifically is involved in roughly 30% of human cancers[1].Ras proteins are part of complex, multifaceted signal transduction pathways that eventually lead to a these growth and proliferation signals which are transmitted via the nucleus.What exactly does signal transduction involve?Signal transduction is essentially the transmission of a signal from the outside of a cell to the nucleus inside. This signal results in alterations in cell metabolism, gene transcription (protein expression), and/or cell shape.There is generally a large amplification in signal as the agonist (binding signal) initially either binds on the outside of a cell membrane (as is the case for large hydrophilic molecules that will not be able to cross the hydrophobic phospholipid cell membrane) or on the inside of the cell (as is the case for hydrophobic steroid molecules that can cross the membrane with ease). This agonist causes a signal to be transmitted all the way to the nucleus. A signal agonist can cause an amplification in signal up to a million fold with ease.These pathways can be executed through a myriad of different cell receptors and pathways, some with higher levels of complexities and amplifications than others. For the purpose of our discussion, there are two main types of receptors: GPCR (G-protein coupled receptors) and RTK (receptor tyrosine kinases). The latter are much more heavily involved in growth, cell differentiation, etc. Both are involved in Ras activation.After the initial agonist binding to the receptor there is a few steps that are required for this signal to be transmitted which different slightly based on GPCR/RTK activation:Ligand -- Receptor -- Transducer/Effector -- Effector -- 2nd Messenger/Protein Kinase1) Ligand (agonist) binds to receptor. This can be done with an extra or intracellular receptor as previously described depending on the hydrophilic or hydrophobic characteristics of the ligand. In GPCRs this is a simple protein receptor, but with RTKs there can be an enzymatic activation of two protein receptors that causes them to link together and activate themselves and form one enzymatically linked receptor.2) Receptor sends the message to the transducer/effector, which then binds some sort of messenger to send the signal along. This is usually done by the phosphorylation of a protein that will carry this message forward. The point is that an activation must occur. Ras is activated by a protein called GEF and inactivated by a protein called GAP. This activation is rerather quickly in normal circumstances. In GPCRs this involves activation of a three subunit protein, whereas in RTKs it involves adaptor proteins that recruit the next protein required in the pathway.3) The transducer/effector (in this case Ras) sends the message to the last step of the pathway before the signal reaches the nucleus, the protein kinase pathway. This pathway (in this case the Raf/MEK/ERK pathway, also known as the MAP KKK pathway) will transduce the signal to the nucleus.Where do the problems arise?As you know, Ras is a small GTPase class of protein, and is a part of the signal transduction pathway which activates the protein kinase pathway and leads to the signal ultimately being transmitted. This activation is initially carried out through the GPCR or RTK and is turned off through a negative feedback loop from the products of the Ras pathway at the receptor/adaptor level. This normally stops the activation of the transducer/effector Ras.The problem arises when mutations in Ras occur - and they occur quite often in cancer patients. Once a mutation in Ras has occurred, it becomes permanently turned on and the pathway does not cease to stop. Even if the adaptor proteins or receptors receive the signal to stop activity it does not matter because Ras itself has mutated to decrease its own GTPase activity. As the exchange of GTP for GDP and the subsequent GTP hydrolysis stops due to the mutation, GTP stays bound to the Ras protein and unregulated cell proliferation and growth ensues. Not only does GTPase activity decrease, but the Ras protein loses sensitivity to GAP (one of the regular inhibitors of Ras)[2][3][4] and is exposed to a larger quantity of GEF (one of the regular activators of Ras through GTP binding)[5][6]. Thus, we can say that the problems arise through 3 main mechanisms:1) Mutations in the Ras protein itself that lead to decrease GTPase activity, and therefore a constantly bound GTP molecule and permanent activation of Ras.2) Overactivation of the wild-type protein that leads to the production of GEF.3) Loss of GAP function due to the decreased sensitivity of the Ras protein.So why can't we inhibit Ras once it has mutated?Pharmaceutical companies have been spending billions of dollars in trying to inhibit Ras once it has been mutated. However, these companies have had only minimal success, if any at all. The first approach has been taken in regards to the disrupting the Ras to GTP binding, but none have succeeded.1) Using competitive inhibitors for the enzymatic active site of Ras. This actually backfired because any molecule that could function to do this would actually further impede any potential GTPase activity. This inactivity gives Ras its oncogenic activity in the first place. Regardless, the only molecules that have been found to achieve this function are clostridial cytotoxins (a type of bacterial toxin), and these toxins work enzymatically to create a Ras protein that is covalently modified, causing Ras to become resistant to GAP entirely. Using an molecule to do the opposite, creating an agonist, would be very difficult (restoring GAP sensitivity or GTPase activity) and it has been shown that it may not be feasible at all[7].2) Developing a drug in attempt to displace GTP from Ras. This has proven a dead end road due despite its promising nature. Due to the high kinetic affinity between the binding of Ras to GTP, the ATP binding site drug competitors on the market cannot compete (micro molar vs nano molar affinities). Disrupting the Ras to GTP high affinity binding has been characterized as "undruggable" in a recent 2022 study[8]. There is still enthusiastic chatter in this arena but so far no one has further succeeded in this task.Some have also tried to disrupt the upstream GEF activator protein (SOS in the previous image)[9][10]. However, nothing yet has been developed to show major promise.This has left us with the absence of an obvious molecule on the level of Ras to target. The next focus has been involved in the construction of Ras itself.Post-translation covalent protein modifications are essential to the formation of Ras, and so it has been suggested that it may be a good target to go after the tools involved in those modifications - specifically farnesyl transferase. Theoretically, disruption of the proteins post-translational modifications would result in a non-functional protein. Furthermore, it was hypothesized that the presence of inactive Ras would act as an inhibitor to previously active Ras signalling through the sequestering of molecules to the proper sub cellular locations involved in its signalling pathways.This approach has involved using farnesyl transferase inhibitors (FTIs). A couple of these FTIs actually made it all the way to phase 3 clinic trials after showing promising results before it was shown to lack the anticipated anticancer activity[11].So why did this not work? Most likely because they drugs were developed using a mutated version of an isoform of Ras. The belief was that all isoforms of Ras would respond similarly, but that unfortunately is not the case. It has been shown that the active in vivo isoforms of Ras become geranylgeranylated in cells in the presence of FTIs, which allows them to bypass the action of the FTIs and develop fully. Nothing further has been developed in this area, but it is possible that FTIs will produce benefits in the future.Another focus has been on Ras at the expression level. In other words, scientists have been trying to reduce the expression of particularly harmful isoforms.Targets for this approach include promoters of specific isoforms of Ras such as the guanine-rich sequence forming a G-quadruplex structure which has been confirmed in human DNA[12]. Many drugs are already available on the market which can bind and stabilize these G-quadruplex DNA structures and can regulate expression of Ras in vitro. However, regulatory activity of these structures can be negative or positive in vivo depending on the isoform of Ras. Also the sequences that are compatible with these structures are widespread within human DNA. Therefore it is unlikely that this will pra proper mechanism for stopping Ras.Pieces of regulatory RNA called microRNAs (specifically microRNA-622) are also being tested which have been shown to decrease specific isoforms of Ras. It is unknown how efficacious this path will turn out to beThe last major focus has been with the protein kinase pathway. Inactivating the MAP KKK pathway you have previously learned about would cause the Ras signal to cease before it could cause any damage. A major problem with this approach is that it is so far downstream from the source of the problem.Since the oncogenic signal from Ras is transmitted through multiple pathways it has been speculated that this will not prove to be very effective[14][15][16][17][18][19][20]. Despite this, FDA approval of one of these inhibitors (trametinib) has been granted. Another MAP KKK inhibitor, MEK162, has shown promising results also in melanoma patients[13].For this approach to be effective the MAP KKK signally pathway would have to predominate the signal transduction pathway from Ras. Another problem with this approach is that resistance could easily emergence with these inhibitors.There are other newer methods being developed of Ras, but it's unclear if any will prove to be useful at this point. Scientists are continually still working to stop Ras and will most likely continue to do so until they find a way as the benefits of such a discover would have a very high payoff for humanity.What happens if we do block Ras?There will still be complications even if we do find a way to simply block the actions of Ras, as Ras is involved in widespread functions in the human body.To give one example, it has been shown that Ras is part of an important pathway for synaptic remodelling in the human brain (the very process that underlies memory)[21]. Mutations in regulators of Ras in neutrons are found in patients with non syndromic mental retardation[22]. There is also evidence that the H-Ras isoform is involved in control of synaptic plasticity[23].This is just one more example in the challenges that we still have yet to face in blocking Ras.References:A. T. Baines, D. Xu, and C. J. Der, “Inhibition of Ras for cancer treatment: the search continues,” Future Medicinal Chemistry, vol. 3, no. 14, pp. 1787–1808, 2022. J. B. Gibbs, I. S. Sigal, M. Poe, and E. M. Scolnick, “Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 18, pp. 5704–5708, 1984.G. Bollag and F. McCormick, “Differential regulation of rasGAP and neurofibromatosis gene product activities,” Nature, vol. 351, no. 6327, pp. 576–579, 1991.U. Krengel, I. Schlichting, A. Scherer et al., “Three-dimensional strucutures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules,” Cell, vol. 62, no. 3, pp. 539–548, 1990.K. Zhang, A. G. Papageorge, and D. R. Lowy, “Mechanistic aspects of signaling through Ras in NIH 3T3 cells,” Science, vol. 257, no. 5070, pp. 671–674, 1992.R. R. Mattingly and I. G. Macara, “Phosphorylatlon-dependent activation of the Ras-GRF/CDC25(Mm) exchange factor by muscarinic receptors and G-protein?? subunits,” Nature, vol. 382, no. 6588, pp. 268–272, 1996.K. Scheffzek, M. R. Ahmadian, W. Kabsch et al., “The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic ras mutants,” Science, vol. 277, no. 5324, pp. 333–338, 1997.T. Tanaka and T. H. Rabbitts, “Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth,” Oncogene, vol. 29, no. 45, pp. 6064–6070, 2010.T. Maurer, L. S. Garrenton, A. Oh et al., “Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 14, pp. 5299–5304, 2012.Q. Sun, J. P. Burke, J. Phan et al., “Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation,” Angewandte Chemie International Edition, vol. 51, pp. 6140–6143, 2012.A. M. Tsimberidou, C. Chandhasin, and R. Kurzrock, “Farnesyltransferase inhibitors: where are we now?” Expert Opinion on Investigational Drugs, vol. 19, no. 12, pp. 1569–1580, 2010.G. Biffi, D. Tannahill, J. McCafferty, and S. Balasubramanian, “Quantitative visualization of DNA G-quadruplex structures in human cells,” Nature Chemistry, vol. 5, pp. 182–186, 2013.P. A. Ascierto, D. Schadendorf, C. Berking et al., et al., “MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study,” The Lancet Oncology, vol. 14, pp. 249–256, 2013.K. R. Stengel and Y. Zheng, “Essential role of Cdc42 in Ras-induced transformation revealed by gene targeting,” PLoS ONE, vol. 7, Article ID e37317, 2012.N. Mitin, K. L. Rossman, and C. J. Der, “Signaling interplay in ras superfamily function,” Current Biology, vol. 15, no. 14, pp. R563–R574, 2005.A. V. Patel, D. Eaves, W. J. Jessen et al., et al., “Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target,” Clinical Cancer Research, vol. 18, pp. 5020–5030, 2012.S. Eser, N. Reiff, M. Messer et al., et al., “Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer,” Cancer Cell, vol. 23, pp. 406–420, 2013.H. Y. Chow, A. M. Jubb, J. N. Koch et al., et al., “p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model,” Cancer Research, vol. 72, pp. 5966–5975, 2012.R. E. Menard and R. R. Mattingly, “Cell surface receptors activate p21-activated kinase 1 via multiple Ras and PI3-kinase-dependent pathways,” Cellular Signalling, vol. 15, no. 12, pp. 1099–1109, 2003.Q. Li and R. R. Mattingly, “Restoration of E-cadherin cell-cell junctions requires both expression of E-cadherin and suppression of ERK MAP kinase activation in ras-transformed breast epithelial cells,” Neoplasia, vol. 10, no. 12, pp. 1444–1458, 2008.E. J. Weeber and J. D. Sweatt, “Molecular neurobiology of human cognition,” Neuron, vol. 33, no. 6, pp. 845–848, 2022. L. B. Rosen, D. D. Ginty, M. J. Weber, and M. E. Greenberg, “Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras,” Neuron, vol. 12, no. 6, pp. 1207–1221, 1994.K. A. Rauen, “HRAS and the Costello syndrome,” Clinical Genetics, vol. 71, no. 2, pp. 101–108, 2007.
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