Computer systems organization and architecture carpinelli pdf free download

These translocate to the nucleus, where they influence the activity of various transcription factors. Production of PtdIns 3,4,5 P3 creates a docking site for Akt. Once compartmentalized at the inner side of the plasma membrane, Akt becomes activated and phosphorylates several substrates involved in cell proliferation, survival and the regulation of cell size. Thereafter, each STAT3 moiety homodimerizes, using its SH2 domain to recognize the phosphotyrosine of its partner, and translocates to the nucleus to operate as a transcription factor.

In all diagrams, dashed lines indicate that the signalling intermediates between the two nodes have not been characterized in detail. These inhibitors are ubiquitylated and degraded by proliferation or differentiation FIG. Prompt sequestration of the activated are unknown Trafficking to the lysosomes is triggered by ligand- Regulation of MET signalling induced activation of MET, and requires the function it is well established that signal transduction pathways that of casitas b-lineage lymphoma Cbl , an E3 ubiquitin- are downstream of tyrosine kinase receptors are modu- protein ligase that is recruited to a juxtamembrane phos- lated not only by the identities of protein—protein inter- photyrosine residue in the active receptor Tyr 86 actions but also by the colocalization of signal transducers FIG.

This leads to MET being monoubiquitylated at in membrane domains or, more broadly, in organelles and multiple sites87, which enables its recognition by endo- vesicles This notion has been recently applied to MET: cytic adaptors that contain ubiquitin-binding domains, the prevailing view that the activated receptor recruits its sorting into clathrin-coated areas at the cell surface signalling effectors at the plasma membrane, which in and its delivery to the endosomal network.

From these turn stimulate diffusible intermediates in the cytosol, has sorting endosomes, MET accumulates on the limiting now been expanded by the finding that MET signals can and internal membranes of multivesicular bodies.

This also emanate from endosomal compartments. Moreover, terminates signalling by sequestering MET from the the levels of MET expression at the cell surface are finely cytosol and preventing it being recycled by the plasma tuned by other spatially restricted events, including extra- membrane.

Finally, the multivesicular bodies fuse with cellular shedding, intracellular cleavage and ubiquitin- the lysosomes and MET undergoes proteolytic demoli- mediated degradation.

All of these processes regulate the tion88, Seemingly active MET is not polyubiquitylated, strength of MET activation and the ensuing robustness of and is therefore unlikely to be targeted for degradation Endosomal MET-dependent signals. MET internalization can promote signalling. Following see below. Here, MET triggers the sustained SH3KbP1 — endophilins, a family of proteins that assist of extracellular material and plasma membrane proteins activation of ErKs, which are then relocated to focal the negative curvature, invagination and scission of the from the cell surface to complexes, where they mediate HGF-induced cell migra- planar plasma membrane during the early phases of intracellular organelles tion probably by phosphorylating paxillin and other focal endocytosis Therefore, Cbl promotes the physical known as endosomes.

A crucial regulator of this endosomal internalization of MET while tagging it for lysosomal signal compartmentalization, and the consequent trans- degradation91 FIG. A cellular structure that links, From the peripheral endosomes, MET traffics along What skews the MET fate towards degradation rather through integrin receptors, the the microtubule network and accumulates in a nondegra- than signalling remains unknown.

This jux- gested that endosomal signalling predominates under cytoskeleton inside the cell. An enzyme that is responsible MET-triggered phosphorylation of STAT3 at the plasma A similar scenario might also apply to MET but a for- for the conjugation of ubiquitin membrane or early endosomes is likely to be below the mal demonstration of such a mechanism has not been to substrate proteins.

Multivesicular body activity of phosphotyrosine phosphatases that dissi- An endocytic intermediate pate STAT3 signal intensity during protein diffusion.

Regulated proteolysis of MET. The first step is a disintegrin and metalloprotease contains small vesicles and is surrounded by a limiting the nucleus, which shields STAT3 against phosphatase AdAM -mediated release known as shedding of membrane.

Although plasmic tail. After being internalized from the cell surface, MET also known as HGF receptor can maintain a signalling-competent modality or can be demolished. In these compartments, the activity of phosphotyrosine phosphatases, which work on signal transducer and activator of transcription 3 STAT3 to dissipate signal intensity, is low. CBL also associates with endophilins through the scaffold molecule CBL-interacting protein 85 CIN85 , which promotes changes in the plasma membrane that are necessary for cell surface curvature in the early phases of endocytosis.

Following endocytosis and intermediate accumulation in multivesicular bodies, MET is subjected to lysosomal degradation. Dashed lines indicate that the signalling intermediates between the two nodes have not been characterized in detail. Specificity-switch mutants, in cell surface but also generates a decoy moiety that inter- which the MET multifunctional docking site has been acts with both HGF by sequestering the ligand and converted into an optimal binding motif for Pi3K, full-length MET by impairing dimerization and trans- Src or Grb2, exhibit a rescue of defined phenotypes activation of the native receptor to further inhibit MET when compared with Met-null animals in line with signalling , Therefore, the use of targeted agents — the effectors that are recruited.

Mice in which MET such as mAbs, which increase MET shedding from the exclusively associates with Grb2 are viable, fertile and cell surface — could have a great therapeutic effect on apparently normal — indicating that Grb2 is sufficient cancers by reducing MET signalling. However, although To secure output production and to increase functional incompatible with survival, individual activation of Src versatility in the face of recurring perturbations, tyrosine is sufficient to restore proliferation of placental tropho- kinase receptors often expand and diversify individual blasts and myoblasts, and selective activation of Pi3K components of their downstream signalling networks, is sufficient to promote axon outgrowth and branching degenerate connections and duplicate entire modules of specific motor nerves Together, these findings of protein—protein interactions.

Signal redundancy, suggest that MET-mediated developmental events are reciprocal signal reinforcement and feedback loops are accomplished by qualitatively different signals that are stereotypical aspects of signal transduction Signal compensation by — albeit in a slightly attenuated form — indicating other transducers that have overlapping functions must that GAb1 has an essential role in MET-based signal be considered.

As mentioned above, cell- and tissue-specific activities seem to be fulfilled by GAb1 associates with MET directly, through a specific dedicated signalling cascades, with some transducers MbS, and indirectly, through the Grb2 adaptor 51, Here, we outline biological outcomes in vivo in a tissue-specific manner: a number of genetic and pharmacologic studies that both direct and indirect interactions with MET are nec- have contributed to this knowledge.

The coverage is essary for functional MET signalling during liver and purposefully not exhaustive: we will limit our attention placenta formation, whereas either the Grb2 binding to those settings in which a more documented connec- site or the MbS, but not both, are required for limb tion between signals and phenotypes has been provided, muscle development Similar to those observed for as well as to those for which information has become MET, interactions of GAb1 with specific downstream available only recently.

MET signalling in embryonic devel- in Hgf- or Met-null embryos, the liver is considerably opment is mainly channelled by the GAb1—SHP2 reduced in size and the placental labyrinth is severely interaction; indeed, GAb1 mutants that are unable to hypomorphic— FIG.

This hypomorphic phenotype bind SHP2 phenotypically copy Met-null mutants, with eventually leads to death in utero owing to compromised defects such as a thin placental labyrinth layer FIG.

Again, and fetal blood. The HGF—MET system also has a deci- we can conclude that the biological responses elicited Placental labyrinth sive role in the proliferation and motility of long-range by GAb1, like those elicited by MET, have different sig- The area of direct exchange between the fetal and migrating muscle progenitors. These myogenic precur- nal requirements in different tissues during embryonic maternal blood supply in the sors delaminate from the dermomyotome, a structure development.

The signalling mechanisms that Hypaxial muscle to form a subset of the hypaxial muscles Ablation of mediate MET-driven tissue patterning during organ Skeletal muscle that is derived from progenitor cell the Hgf or Met genes results in complete absence of this regeneration have been studied both in vitro, by per- populations that are located in specific muscle type, leaving all other muscle groups forming morphogenetic assays under three-dimensional the lateral myotome of each unaffected— Examples of hypaxial tion affects the proper wiring of the nervous system, conditional deletion of MET in selected tissues.

HGF causes sphe- the early formation of extensions and chains, seem to be roids to form elongated tubules in a stepwise sequence necessary to produce cords and hollow tubules HGF of biological events First, cells undergo a partial has an important role in the regulation of the functions epithelial—mesenchymal transition EMT , which involves of MMPs by enhancing the transcriptional levels of a the transformation of tightly packed elements into large number of MMPs as well as those of several pro- invasive, spindle-shaped cells that emit long cytoplas- teases that convert the precursor forms of MMPs into mic extensions in the surrounding matrix.

Then, these active enzymes— Production cords that become mature tubules by the progressive of HGF increases steeply following liver damage, and formation of a continuous lumen.

At the signalling the ensuing activation of MET in hepatocytes provides level, the series of events required for HGF-dependent strong mitogenic and anti-apoptotic stimuli for organ tubule formation has been dissected. As a whole, this repair 14,15, The prolifera- EMT. The transformation of REFS 44,53,, Cell survival is promoted by trans- tion defect is reflected by low transcriptional induction an epithelial cell into a mesenchymal cell that has cription factors of the Snail family The later phases of cyclins and enhanced expression of the cyclin- migratory and invasive of epithelial tubulogenesis entail the activity of matrix dependent kinase CdK inhibitor p21 also known properties.

Mutant mice with targeted disruption of hepatocyte growth factor HGF; also known as scatter factor - or MET also known asNature Reviews Molecular Cell HGF receptor -dependent Biology signals show various abnormalities that are related to proliferative impairment. Similarly, the labyrinth layer delimited by dotted lines contains fewer trophoblast cells, embryonic vessels and maternal sinuses and more mesenchymal cells.

The junctional zone denoted by an asterisk lies above the labyrinth. A similar decrease of proliferating hepatocytes can be observed during post-hepatectomy regeneration in mice with liver-specific knockout of GAB1 and in mice with liver-targeted disruption of SHP2 REF.

Images in part b modified, with permission, from REF. Images in part c modified, with permission, from REF. Images in part d modified, with permission, from REF. At MET also displays a similar protective activity in least in the liver, fibrosis is further reduced by an atypical the kidney. At pro-survival pathway and, subsequently, the transcrip- the wound edges, marginal keratinocytes form the so- tional upregulation of the anti-apoptotic effectors b-cell called hyperproliferative epithelium, which undergoes lymphoma-extra large bCl-Xl and bCl-2 REF.

Keratinocytes kidney regeneration. Moreover, way for the development of several therapeutic strategies HGF fosters the proliferation and migration of epithelial together with, or as an alternative to, the selective inhi- cells into the de-epithelialized zone.

The major signal- bition of MET. However, recent data suggest that this is ling effectors that mediate these processes are GAb1, unlikely to be the case. The contribu- interventions, One could speculate that an can be recapitulated only when both effectors are con- imbalance in substrate dephosphorylation might lead to comitantly associated with MET, Thus, combined the silencing of some MAPK components while leaving activation of multiple pathways is necessary to instruct others relatively unaffected.

However, blocking a single network node is steady-state signalling due to chronic receptor activation, sufficient to perturb cellular responses, indicating that which is the consequence of a fixed and transmissible the targeted inhibition of a specific signalling pathway genetic alteration; in this setting, the reliance of tumours cannot be compensated for by other, still active, regula- on the continued activity of MET seems to be governed tory tiers.

This is in line with the well-established obser- by a small, self-sufficient group of signal transducers. For conditions that are typical of cancer; in this situation, example, the integrity of JNK- and pdependent MET-regulated outcomes are controlled by multiple, signals is required for MET-stimulated proliferation and non-redundant signalling crosstalks.

The notion that inhibiting a single transducer will suffice to revert or impair the biological phenotype Outlook induced by MET activation has strong implications. The organ repair and contrast fibrotic evolution, agents that regulation of the different outcomes of MET activation, are endowed with agonistic activity are currently being as well as the definition of their biological specificity, tested in a number of early-phase clinical trials. From an could depend on signal modifiers that are endowed with opposite perspective, several MET inhibitors are being a tissue-restricted distribution including, as recently evaluated for their efficacy in blocking the growth and demonstrated, microrNAs— or on dedicated pro- progression of various tumour types Most anti-cancer tein interaction networks, and could be further tuned therapies are accompanied by drug-induced toxicity that by transcriptional modulation.

Cell- and context-dependent signal MET-activating compounds in cancer patients would pro- modulators can be now identified by using genome- mote the spread of neoplastic cells and awaken dormant wide functional screens; higher details in regulatory metastases Even more insidiously, MET-driven stimu- protein—protein interactions can be achieved by using lation of growth and survival signals might cause the pro- mass spectrometry; and, finally, information on the gression of incipient pre-malignant clones to full-blown presence of positive or negative signalling feedback malignancy in apparently healthy individuals.

Bryant, D. From cells to organs: encoded by the proto-oncogene c-MET. Oncogene 6, Michalopoulos, G. Liver building polarized tissue. Nature Rev. Cell Biol. Science , 60—66 Naldini, L. Scatter factor and hepatocyte growth Bhowmick, N. Gurtner, G. Wound repair and regeneration.

EMBO J. Nature , — Weidner, K. Evidence for the identity of Mars, W. Frisch, S. Anoikis mechanisms. Natl Acad. Lu, P. Patterning mechanisms of branched Science , — Birchmeier, C. Developmental roles of Owen, K. Pericellular activation of hepatocyte 5. Zaret, K. Trends Cell Biol. Cancer as an overhealing Vande Woude, G. Met, metastasis, motility and Ponzetto, C. A multifunctional docking site Cell Biol.

Yang, J. Epithelial-mesenchymal Comoglio, P. Publication Type. More Filters. Highly Influenced. View 4 excerpts, cites methods and background. View 1 excerpt. Computer Architecture and Organization deals with both software and hardware aspects of computer systems.

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SeoMaster February 24, at AM. Load more Subscribe to: Posts Atom. Filed By:. Motion Info: Please select Filed Date:. Petitioner resume Se Confirmation Notice. Francis Boyle, who Se Confirmation Notice. Anthony F Governor Hochul announcement of Se Confirmation Notice. Respondent Peter Daszak, PhD. Posted Jan. NYS C. The court is in receipt of your filings, on September 27 and 30, , of a summons, two affidavits and exhibits 14 to 20 to the petition that you submitted by order to show cause on September 11, , which order this court declined to execute.

Please note that the court's. In order to move this case forward, you must effect such service. Absent such service and proof thereof, this court is without jurisdiction over the named defendant's and cannot reach your claims until each respondent has had an opportunity to respond. Very truly yours,. Gordon W. Eddy Principal Law Clerk to Hon.

Martin D. Please keep this notice as a confirmation of this filing. Filing User Christopher E Strunk strunk leader. Pamela J. Vogel, Warren County Clerk - vogelp warrencountyny. Timothy E. Murphy, Lynn M. Cuomo; Howard A. Chokshi, MD, MSc. DiNapoli; and those et al. Massachusetts, U. The Court's decision articulated the view that individual liberty is not absolute and is subject to the police power of the state.

That Massachusetts was one of 11 states that had compulsory vaccination laws going back to the time of Benjamin Franklin. Bell, U. It was widely believed to have been slightly weakened by Skinner v. Oklahoma U. The Americans with Disabilities Act of has also made guaranteed protections from the federal government to people with disabilities, including the intellectually disabled.

United States, U. The decision has widely been criticized, with some scholars describing it as "an odious and discredited artifact of popular bigotry" and as "a stain on American jurisprudence". Even Chief Justice John Roberts explicitly repudiated the Korematsu decision in his majority opinion in the case of Trump v. The case is often cited as one of the worst Supreme Court decisions of all time. Roosevelt had issued Executive Order on February 19, , authorizing the War Department to create military areas from which any or all Americans might be excluded.

Subsequently, the Western Defense Command, a United States Army ordered "all persons of Japanese ancestry, including aliens and non-aliens" to relocate to internment camps. However, a year-old Japanese-American man, Fred Korematsu, refused to leave the exclusion zone and instead challenged the order on the grounds that it violated the Fifth Amendment.

Petitioner contends the State and its Corporate Partners illegally coerce Experimental shots during a time of peace not a kinetic war for a questionable disease illegal bio-warfare propaganda threaten to lock up and punish those rejecting a shot without being given data proof of safety and effectiveness are denied informed consent rights for depopulation and unjust enrichment.

Petitioner offers his own linguistic ranking of statements made and or attributed to historical figures who have shaped the events taking place presently, notwithstanding published reports and global conferences shaping the present events; and that Petitioner contends is a useful tool to glimpse at the long term state of mind impact of those listed below.

If it happens, you can bet it was planned that way. When in doubt, don't. Hunger is the best pickle. Honesty is the best policy. Lost time is never found again. You may delay, but time will not. Well done is better than well said. One today is worth two tomorrows. Where liberty is, there is my country. Diligence is the mother of good luck. God helps those who help themselves. He that lives upon hope will die fasting. Whatever is begun in anger ends in shame. Energy and persistence conquer all things There was never a good war, or a bad peace.

By failing to prepare, you are preparing to fail. Rebellion against tyrants is obedience to God. A place for everything, everything in its place. When you're finished changing, you're finished. If passion drives you, let reason hold the reins. Guests, like fish, begin to smell after three days. Wise men don't need advice. Fools won't take it. He that can have patience can have what he will. Three can keep a secret, if two of them are dead.

Some people die at 25 and aren't buried until He who falls in love with himself will have no rivals. An investment in knowledge pays the best interest. Never leave that till tomorrow which you can do today. I didn't fail the test, I just found ways to do it wrong. Life's tragedy is that we get old too soon and wise too late. Beware of little expenses.

A small leak will sink a great ship. A false friend and a shadow attend only while the sun shines. Experience keeps a dear school, but fools will learn in no other. Keep your eyes wide open before marriage, half shut afterwards. Do not fear mistakes.

You will know failure. Continue to reach out. Any fool can criticize, condemn and complain - and most fools do. Being ignorant is not so much a shame, as being unwilling to learn. Either write something worth reading or do something worth writing. Don't throw stones at your neighbors if your own windows are glass.

Wine is constant proof that God loves us and loves to see us happy. He that is good for making excuses is seldom good for anything else.

Early to bed and early to rise makes a man healthy, wealthy and wise. In this world nothing can be said to be certain, except death and taxes. Tell me and I forget. Teach me and I remember. Involve me and I learn.

Hide not your talents. They for use were made. What's a sundial in the shade? At twenty years of age the will reigns; at thirty, the wit; and at forty, the judgment. There are three things extremely hard: steel, a diamond, and to know one's self. Dost thou love life? Then do not squander time, for that is the stuff life is made of. We must, indeed, all hang together or, most assuredly, we shall all hang separately. It takes many good deeds to build a good reputation, and only one bad one to lose it.

It is the working man who is the happy man. It is the idle man who is the miserable man. Tricks and treachery are the practice of fools, that don't have brains enough to be honest. The Constitution only gives people the right to pursue happiness. You have to catch it yourself. Be at war with your vices, at peace with your neighbors, and let every new year find you a better man.

They who can give up essential liberty to obtain a little temporary safety deserve neither liberty nor safety. The U. Constitution doesn't guarantee happiness, only the pursuit of it. You have to catch up with it yourself. Without continual growth and progress, such words as improvement, achievement, and success have no meaning.

Without freedom of thought, there can be no such thing as wisdom - and no such thing as public liberty without freedom of speech. Remember not only to say the right thing in the right place, but far more difficult still, to leave unsaid the wrong thing at the tempting moment.

Money has never made man happy, nor will it, there is nothing in its nature to produce happiness. The more of it one has the more one wants. I am for doing good to the poor, but I differ in opinion about the means. I think the best way of doing good to the poor is not making them easy in poverty, but leading or driving them out of it.

Hate is more lasting than dislike. Great liars are also great magicians. Strength lies not in defence but in attack. The day of individual happiness has passed. Words build bridges into unexplored regions. The victor will never be asked if he told the truth. Success is the sole earthly judge of right and wrong. Who says I am not under the special protection of God? I use emotion for the many and reserve reason for the few. I do not see why man should not be just as cruel as nature.

Humanitarianism is the expression of stupidity and cowardice. What good fortune for governments that the people do not think. It is always more difficult to fight against faith than against knowledge. How fortunate for governments that the people they administer don't think. Anyone who sees and paints a sky green and fields blue ought to be sterilized. Any alliance whose purpose is not the intention to wage war is senseless and useless. I believe today that my conduct is in accordance with the will of the Almighty Creator.

The great strength of the totalitarian state is that it forces those who fear it to imitate it. It is not truth that matters, but victory. He alone, who owns the youth, gains the future. The broad masses of a population are more amenable to the appeal of rhetoric than to any other force. The leader of genius must have the ability to make different opponents appear as if they belonged to one category.

Universal education is the most corroding and disintegrating poison that liberalism has ever invented for its own destruction. Generals think war should be waged like the tourneys of the Middle Ages. I have no use for knights; I need revolutionaries. The art of leadership How many divisions has he got?

No man - no problem. Why would we let them have guns? Those who count the vote decide everything. When there's no person, there's no problem. The people who count the votes decide everything. Fascism is a religious concept. Every anarchist is a baffled dictator.

The truth is that men are tired of liberty. It's good to trust others but, not to do so is much better. Socialism is a fraud, a comedy, a phantom, a blackmail. The League is very well when sparrows shout, but no good at all when eagles fall out. Democracy is beautiful in theory; in practice it is a fallacy.

You in America will see that some day. Let us have a dagger between our teeth, a bomb in our hands, and an infinite scorn in our hearts. We become strong, I feel, when we have no friends upon whom to lean, or to look to for moral guidance. War alone brings up to their highest tension all human energies and imposes the stamp of nobility upon the peoples who have the courage to make it. Women hold up half the sky. All reactionaries are paper tigers. In waking a tiger, use a long stick. I voted for you during your last election.

Once all struggle is grasped, miracles are possible. Passivity is fatal to us. Our goal is to make the enemy passive. Despise the enemy strategically, but take him seriously tactically.

We shall heal our wounds, collect our dead and continue fighting. Politics is war without bloodshed while war is politics with bloodshed. The guerrilla must move amongst the people as a fish swims in the sea.

Let a hundred flowers bloom, let a hundred schools of thought contend. A revolution is not a dinner party, or writing an essay, or painting a picture, or doing embroidery. Enable every woman who can work to take her place on the labour front, under the principle of equal pay for equal work. Genuine equality between the sexes can only be realized in the process of the socialist transformation of society as a whole. The atom bomb is a paper tiger which the United States reactionaries use to scare people.

It looks terrible, but in fact it isn't. Classes struggle, some classes triumph, others are eliminated. Such is history; such is the history of civilization for thousands of years.

In general, any form of exercise, if pursued continuously, will help train us in perseverance. Long-distance running is particularly good training in perseverance.

We think too small, like the frog at the bottom of the well. He thinks the sky is only as big as the top of the well. If he surfaced, he would have an entirely different view. The cardinal responsibility of leadership is to identify the dominant contradiction at each point of the historical process and to work out a central line to resolve it.

Letting a hundred flowers blossom and a hundred schools of thought contend is the policy for promoting the progress of the arts and the sciences and a flourishing culture in our land.

I have witnessed the tremendous energy of the masses. Mark Zuckerberg 1. People like to talk about war. Move fast with stable infrastructure.

I do everything on my phone as a lot of people do. The only meat I eat is from animals I've killed myself. You get a reputation for stability if you are stable for years. The thing I really care about is the mission, making the world open. My goal was never to make Facebook cool. I am not a cool person.

By giving people the power to share, we're making the world more transparent. If you're always under the pressure of real identity, I think that is somewhat of a burden. I think that people just have this core desire to express who they are. And I think that's always existed. Our mission is to connect every person in the world. You don't do that by having a service people pay for. The thing that we are trying to do at Facebook, is just help people connect and communicate more efficiently.

A squirrel dying in front of your house may be more relevant to your interests right now than people dying in Africa. The basis of our partnership strategy and our partnership approach: We build the social technology. They provide the music. I think a simple rule of business is, if you do the things that are easier first, then you can actually make a lot of progress. The biggest risk is not taking any risk In a world that is changing really quickly, the only strategy that is guaranteed to fail is not taking risks.

Facebook was not originally created to be a company. It was built to accomplish a social mission - to make the world more open and connected. What really motivates people at Facebook is building something that's worthwhile, that they're going to be proud to show to friends and family.

Bill Gates has always been a mentor and inspiration for me even before I knew him. Just growing up, I admired how Microsoft was mission-focused. When I started Facebook from my dorm room in , the idea that my roommates and I talked about all the time was a world that was more open.

I updated my grilling app, iGrill, today and it now has Facebook integration that lets you see what other people are grilling right now around the world. We just think that there are all these different ways that people want to share, and that compressing them all into a single blue app is not the right format of the future. Building a mission and building a business go hand in hand. The primary thing that excites me is the mission.

But we have always had a healthy understanding that we need to do both. A lot of people are focused on taking over the world or doing the biggest thing and getting the most users.

I think part of making a difference and doing something cool is focusing intensely. Just take terrorism, for example. We have a team of more than people working on counterterrorism. I mean, that's pretty intense. That's not like what people think about what Facebook is. Hackathons are these things where just all of the Facebook engineers get together and stay up all night building things.

And, I mean, usually at these Hackathons, I code too, just alongside everyone. I feel that the best companies are started not because the founder wanted a company but because the founder wanted to change the world If you decide you want to found a company, you maybe start to develop your first idea. And hire lots of workers. My goal was never to just create a company.

A lot of people misinterpret that, as if I don't care about revenue or profit or any of those things. But what not being just a company means to me is not being just that - building something that actually makes a really big change in the world.

I hope that Facebook and other Internet technologies were able to help people, just like we hope that we help them communicate and organize and do whatever they want to every single day, but I don't pretend that if Facebook didn't exist, that this wouldn't even be possible.

Of course, it would have. There is a huge need and a huge opportunity to get everyone in the world connected, to give everyone a voice and to help transform society for the future.

The scale of the technology and infrastructure that must be built is unprecedented, and we believe this is the most important problem we can focus on. Think about what people are doing on Facebook today.