Now, this is the first lecture in by 150 on the neuroscience of disease. And most of the lectures from now on will be on that topic. And Ralph and I figure you have a pretty good background in elementary and fundamental neuroscience. And so now it's fun to apply that knowledge to diseases that you might see in your friends. We're going to talk about two neurodegenerative diseases today. Next time we will talk about diseases of emotion. And Ralph will be talking two lectures next week. Actually, he'll be talking about emotion and about other. And I will come and talk with you about schizophrenia as well. The two diseases that we're going to discuss today will be Alzheimer's and Parkinson's. This is Michael J. Fox, who has suffered from Parkinson's disease for many years, the actor. The two diseases Alzheimer's and Parkinson's are the most common neurodegenerative diseases in our society. We are going to follow a general description for all of the neural diseases. We'll talk about the clinical description about the genetics, at least what we know about the genetics. The pathophysiology, patho means sick, physiology means how things function. So how the disease gets started based on what we know about the fundamental problems. Biomarkers, easily accessible biochemical or functioning blood tests or other aspects that will allow us to give a quick summary of a disease so that we can follow both the time course of the disease and the therapy, as well as animal models. There is this interesting concept called a heterozygous advantage. And I won't say much about the heterozygous advantage until we get to one of the psychiatric diseases, bipolar. We'll talk about that in greater detail. And then about therapeutic approaches. So first off is Alzheimer's. And we have a lot to cover today. I hope we can get through it. But the typical case of Alzheimer, all right, now here's the usual question. Who first described Alzheimer's disease? Okay, so Alzheimer's disease usually begins with a rather pure impairment of a person's ability to think and his cognitive ability. Now, as I say to my friends my age, mild cognitive impairment does not always lead to a dementia, to a more severe case of Alzheimer's or other dementia. But there is a progression. First, the only symptom is forgetfulness. And people may have trouble remembering recent events, activities, names of familiar people or things. Maybe they can't do simple math problems. Did I already say that they repeat themselves every few minutes in conversation? No, okay. In the middle stages of Alzheimer's, people forget how to do simple tasks. Brushing their teeth, combing their hair. They can no longer think clearly. They begin to have problems speaking. Third stage, Alzheimer's patients actually may become aggressive or anxious because they are realizing that they have lost so much. They begin to wander away from home and they eventually need total care. Now, there is a scale called the mini mental status exam, which can be administered in a few minutes by either a psychologist or a neurologist or a psychiatrist. And the mini mental status exam says asks, well, the one of the toughest is please count back from 100 by seven. And then there are the simple questions like who's president, what day of the week is it, when were you born. There are a total of 30 questions. Everybody in this room would score 30. Sometime below 25 begin the symptoms and after a while patients score very poorly on the mini mental status exam. So it is, as we say, the most common neurodegenerative disease. And the number of people in age groups are given here. Alzheimer's is not a normal part of aging. And so you cannot say about a person. Well, quite normal to have Alzheimer's at his or her age. Late onset sporadic Alzheimer's occurs. And this is by far the most common late in life, no obvious inheritance. But we'll talk about some risk factor genes that do interact with each other. In fact, the most common risk factor gene to date remains a gene that makes one form of apolipoprotein E, which is a carrier for lipoproteins in the blood. So one polymorphism in APOE4 is in APOE is called APOE4 roughly 16%. And where there where a person has one copy of the gene, the probability of getting Alzheimer's is elevated to copies of the gene very severely all time elevated. Familiar Alzheimer's, which leads almost invariably to Alzheimer's is much rarer. It starts at age 30 to 60. So much earlier that typical hallmark of Alzheimer's pathology are the plaques and tangles in the brain. So here are these amyloid plaques. They contain a large amount of a very famous 42 amino acid peptide called beta amyloid or A beta 42. Now this is not the alpha 4 beta 2 nicotinic receptor. It is called A beta and it's 42 amino acids long. And it may very well be that beta amyloid is the initial cause of the pathophysiology that leads to dementia. Amyloid plaques probably contribute to the later stages. So the plaques are not what's doing the damage. It may be the beta amyloid itself. Then there are also neurofibrillary tangles that have a lot of cytoskeletal proteins, especially the microtubule associated protein tau or tau as most people call it. So in these tangles there are lots of phosphorylated proteins and these two could cause aggregation and precipitation. So it is important to realize that these plaques and tangles, although they are by far the most visible aspect of the disease, are probably not in the causal progression of the disease. They come much later. And in general, people with Alzheimer's have reduced brain volume, especially in regions that we've discussed the endo-rynal cortex and the hippocampus. So what is going on with Alzheimer's? Well, we don't know, but here is amyloid precursor protein APP. There are mutations associated with familial Alzheimer's disease. Now APP is amyloid precursor. These familial Alzheimer's is rather rare. There is also in this complex a protein called presanilin-1, and as we're going to see, presanilin-1 is itself a component of a protein called gamma secretase. So all of these mutations in presanilin-1 or in APP are associated with familial Alzheimer's disease. In addition to the beta amyloid plaques, there are the taupaties as well, and these are mutations in ta. These typically do not lead to a pure Alzheimer's. They cause frontotemporal dementia with Parkinsonism. And apparently within the last week, the comedian who killed himself, Williams, not Brian Williams, Robin Williams, thank you, was revealed to have been suffering from a form of frontotemporal dementia, and it is thought that this may have contributed to his suicide. So how does all of this work? Well, here is the amyloid precursor protein, APP. A beta 40 and 42 are thought to be proteolytic products. So A beta APP has this long extracellular region, has a little bit of a stub of the cytoplasmic region and the transmembrane domain. Within this stub region, there are several sites for proteolytic cuts, and so these are called alpha, beta, and gamma secretase. And then there are also some domains out here that are associated with Alzheimer's disease. And so it is thought that overproduced A beta and A beta 42 eventually arises because an altered ratio of proteolytic cleavages, and so the alpha, beta, and gamma proteolytic cleavages. And in fact, all of the known genetic risk factors proposing to true Alzheimer's disease do increase the accumulation of A beta peptides. And so there are APP mutations themselves on chromosome 21. There's the ApoE4 polymorphism, which we talked about already on chromosome 19, which also seems to increase the density of A beta plaques. There are mutations in PresaNLN1 and PresaNLN2, which increases the production of A beta 42. And there is a recently discovered protein called trim2, which increases the density of A beta plaques. And I believe there is a population in Iceland that has a mutation of trim2 and is actually protected against Parkinson's, sorry, against Alzheimer's. So one needs to understand that the amyloid hypothesis has indeed evolved over the years, and also different scientists have different takes on the amyloid hypothesis. So it was thought originally that these deposits were pathogenic, but it's now thought that A beta, which eventually causes the deposits, micro aggregates or soluble A beta oligomers are the neurotoxic species. And so it's important to realize that although many people publish papers saying, ah, I find that when I overexpress A beta, this molecule is affected, that molecule is affected, this one goes up, this one goes down. There is no clear single target for A beta. However, soluble oligomers, as we say, do apparently cause, which range from 40 to 42 peptides, do appear to interact with other proteins. They are toxic to neurons. It may very well be that the 12-mer is the most significant toxic form, but that changes year by year. And one of the more interesting hypotheses, also which holds for Parkinson's disease, is that misfolded alpha A beta 42 may actually act like a prion. If it develops in one cell, it may spread to another cell. A prion is a protein that seems to be infectious rather than DNA that seems to be infectious. So, what on earth is A beta, is APP there for? What on earth is presanelan there for? It may very well be that the normal function of the secretase and presanelan, which is part of the secretase, is to protealize notch. We learned about notch and delta in signaling. And the proteolysis of APP may be a side effect that also gets protealized. So, in the core gamma secretase complex, there is presanelan, either number one or two. Another protein that we know a little bit about. Another one that we know a little about and yet a third one. So, there's this complex of proteins called the gamma secretase. And it may be absolutely accidental that it cleaves APP, but it almost certainly cleaves notch. So, what are the general cellular processes? Well, here we get into the term for the first time protein homeostasis or proteostasis. And here, we're going to spend a lot of time talking about misfolded proteins today. And they are indeed a major and increasing theme in neurodegenerative disease. My lab is interested in them. Typically, when misfolded proteins accumulate, they do so in the endoplasmic reticulum. And this causes endoplasmic reticulum stress and a phenomenon called the unfolded protein response in which the cell responds homeostatically to the presence of lots of unfolded proteins in the ER. Now, ordinarily, the cell has mechanisms that overcome that. And we'll see a beautiful graph of that in a few slides. But if the unfolded protein response goes on too long, it becomes apoptotic. That is, cells begin to die. Then, there is also the usual hypothesis having to do with calcium, which is that excited toxicity occurs because the cell is stimulated too much because its channels are open too much. Calcium accumulates and eventually overwhelms the cell's ability to pump it out. And this allows various metabolites to accumulate in wrong compartments. And calcium also activates transduction systems, overactivates enzymes, and this causes necrosis of the cell. The cell dies. So, there are these two general hypotheses in which an insult can be caused either by misfolded proteins or the somewhat older hypothesis in which hyper-excitability, excited toxicity causes cell death, and both may be operative. Here's a, we're harking back now to our lecture on LTP and on learning and memory. Here's an example, a very specific example of how the beginning stage of Alzheimer's may be interfering with cognitive processes. And so, this is A-beta injected into a slice of the hippocampus, and people are monitoring long-term potentiation. So, here is a cell line that has been engineered to express A-beta. So, it's secreting A-beta into the medium. One takes the medium from that cell line, conditioned medium from this culture dish over here. And one puts it onto the slice that is being assessed for LTP. So, the conditioned medium containing A-beta oligomers decreases LTP, but the conditioned medium from another cell line next door that's also secreting lots of stuff, but has not been infected with A-beta and is therefore not secreting A-beta, doesn't have this effect. So, this is wild type CM conditioned medium. And there are a couple of other controls in the lower panel having to do with antibodies against A-beta. So, this is a highly specific and well controlled experiment showing that too much A-beta can indeed interfere with a model for a cognitive process. So, what are animal models for Alzheimer's? Probably the best animal models are mice that overexpress APP, amyloid precursor protein, especially mice that overexpress APP with Alzheimer's disease associated mutations, point mutations. Now, the question becomes, well, what about biomarkers for Alzheimer's? I've told you about the mini-metal status exam, the neurological slash psychiatric exam. And that is usually quite accurate in diagnosing dementia. But really for Alzheimer's, only an autopsy is the right way to do it, and only an autopsy shows decrease in the brain areas such as the basal forebrain, the hippocampus, and the entorhinal cortex. So, can you come up with a biomarker? Well, so various people are trying to do proteomics and metabolomics on cerebrospinal fluid, on the fluid in the ventricles, hoping to find a pattern that distinguishes a patient with Alzheimer's disease that would be much easier and more quantitative than waiting to autopsy, obviously. It might not be easier than a mini-metal status exam, but it's more objective. And then there are getting to be pet markers for APP deposits. Here is one of them. It's called Floor Beta Peer. Beta obviously is for beta amyloid. And this very careful paragraph, which you can read yourself, says, okay, we have FDA approval to give this pet test. And there are words like inconsistent with the neuropathological analysis of AD. So, if there's a negative scan that's inconsistent, if there's a positive scan like this one here, then moderate to frequent neurotic plaques, but not an absolute proof of Alzheimer's, other types of neurologic conditions, as well as older people with normal function. And so, this is a way of hemming and hawing around the fact that there is no biomarker, there is no good imaging procedure for Alzheimer's. We won't discuss heterozygic advantage yet. What about therapeutic approaches to Alzheimer's? Really, there are essentially no good therapeutic approaches. Basal forebrain cholinergic neurons are actually early death in Alzheimer's. And so, they produce acetylcholine. And so, the idea is let's make their remaining acetylcholine last longer and be more protective by using a cholinesterase inhibitor. You remember that acetylcholine esterase is broken down at the nerve muscle synapse by an enzyme acetylcholine esterase. And so, there are some brain penetrant acetylcholine esterases. The three that are on the market most prevalent now have these trivial names, and you will probably know them by their trademarks. A newer one, and so, it's not these work a little bit. They may delay symptoms by a couple of months. Then there are some inhibitors of NMDA receptors on the market. The idea, as you all know, is that NMDA receptors permeate calcium, and so, if you want to stop excited toxicity, you might stop the flow through NMDA receptors. And this is presumably the way the NMDA receptor blockers work. But inhibitors of beta secretase, which ought to be the answer, have pretty much either failed in the clinic or are still in development. And then there are gamma secretase inhibitors, which have failed. So there's a gamma secretase inhibitor, which is supposed to spare the notch system and block APP selectively. They haven't yet succeeded. How about antibodies against beta APP or amyloid beta? So here, biotech companies, including ones that we know well, such as Genentech and Amgen, have tried very hard to make antibodies against either beta APP or amyloid beta. And these have not yet panned out either. So we have a problem. Any questions about Alzheimer's? Okay, let's move on now to Parkinson's, which is the second most prevalent neurodegenerative disease. So we have the usual outline that we're going to apply to this disease. So James Parkinson was something like a dentist in 1817. And he observed these people in London during his daily walks. He found six of them. He called it paralysis agitans, agitated paralysis. So I'm going to show you a video, a YouTube video of a person who I believe is a professor of neurology, but I have not been able to track down this person's name. He does an excellent... This gate is the gate that is hypokinetic gate. The prototype is Parkinson's, a Parkinsonian type of gate in which the patient will have... This gate is the gate that... This gate is the gate that is hypokinetic gate. The prototype is Parkinson's, a Parkinsonian type of gate, in which the patient will have a posture which will be scooped over, leaned forward, and then will have difficulty as far as initiating gate. When the gate is initiated, there are small steps. Oftentimes there's a tremor associated with this. And as the gate progresses, there may be a picking up of speed of what's called a fenestrative gate. And then in turning, as they're having a normal turning, the patient will turn on block, which means they'll turn almost as a statue moving around. And then, again, having difficulty starting and the... Sit at Starbucks and watch people with that description walk by. Sometimes at the red door, we see people walking around campus with such a description also. What is not shown on this video are the small motor movements. The most common is a pill rolling movement, where a person just has his fingers together and does this for a large amount of time, and again, also a little bit of a shaking in the hands. However, one rarely sees this full blown because most Parkinson's patients have either been... have had electrical implants, deep brain stimulation, which we will discuss later in the lecture, or are medicated with Eldopa or another drug. But it's very tricky to get a patient medicated correctly, and sometimes overmedication occurs. And the easiest... You notice that the actor was leaning forward, and overmedicated Parkinson's patient actually leans too far back. They have often helped Parkinson's patients stand upright. Dopamine. The dopamine-ergic neurons in the brain. Here is a sagittal view of the human brain.   So each neuron has a massive amount of axon, releases lots of neurotransmitter, has to work very hard to keep this axon up. In a mouse, I've showed... Now, this is a coronal section through a mouse brain, stained with tyrosine hydroxylase, which is the enzyme that makes dopamine. And so I've told you about the handlebar moustache in the brain, that is the set of neurons which make dopamine. And the handlebars are the substantia nigra. In fact, the substantia nigra pars compacta, because the neurons are fairly close together, and it is the handlebars which degenerate in Parkinson's disease. The upper lip of the handlebar moustache is the ventral tegmental area, still dopamine-ergic neurons, but they are responsible for a sense of pleasure. We'll get back to this concept in a few slides. One, we're going to use this schematic view, which comes from a nice book by Eric Nestler, Steve Hyman, and Rob Malenka of the relations between the basal ganglia and the rest of the brain. So the key here is that there are some excitatory neurons, especially high up in the cerebral cortex, and also in the subthalamic nucleus. While the subthalamic nucleus, it won't surprise you, is below the thalamus. Well, here's the thalamus, the subthalamic nucleus is below it. And in the basal ganglia, there are lots of GABA-ergic neurons. So in order to understand the feedback loop that goes wrong in Parkinson's disease, we actually have to do lots of sine inversions. And sometimes it's really unclear how to do those sine inversions to make things even more challenging that striatum, which has these large neurons called the medium spiny neurons, has two types. In fact, there's two types of neurons, and these two projections were discovered by Malen DeLong, who wrote the chapter, I think it's chapter 43 in Candel. So there is the direct projection from the striatum back to the substantia nigroparse reticulata, which is not dopaminergic, but that feeds to the substantia nigroparse compacta, which is dopaminergic. And then there's an indirect, which has one more synapse. So the signs actually do change. But if you look carefully, this guy has a negative, let's see now, I hope I've got it right, this guy has negative to here, this guy is negative positive, positive, yeah, this guy is positive to here. So in fact, oh, but this is a change sign again. So this is a positive, and this is also a positive. So in both cases, the striatum feeds back in a positive way to the substantia nigroparse compacta. The two types of substantia nigranurans actually had different dopamine receptors on them. One is coupled to GI, the inhibitory G protein, and the other to GS, the stimulatory G protein. So even at the level of the substantia nigra, the dopaminergic projections to the striatum, we have lots of diversity. In the early stage of Parkinson's, people do lose individual dopaminergic neurons, but it may very well be that the remaining dopaminergic neurons sprout, increase their projections, so that the symptoms in early stages of losing Parkinson's disease are not so obvious. And there are various statements that neurologists like to say that Parkinson's does not become evident until people have lost 80% of their neurons. These days you can do a better diagnosis of early stage Parkinson's, so now people say that you begin to note Parkinson's when the patient has only lost 50% of his dopaminergic neurons. And again, as with Alzheimer's, there are inclusion bodies, there are deposits of poorly folded proteins in the cell. This one is called a Lewy body. I won't tell you who discovered the Lewy body. And they occur in dopaminergic neurons primarily, but they also occur in some other diseases. And so there is a disease called dementia with Lewy bodies. Parkinson's doesn't begin with a dementia. It begins as a movement disorder as the YouTube video demonstrated. But there are other signs in early adjuncts of Parkinson's disease. One of the most interesting is that typically 20 years before a patient manifests clinically obvious Parkinson's disease, that patient has constipation. Now I hasten to add to audiences my age that constipation is not a predictor of Parkinson's disease. Retrospectively you can see it, but lots of people have constipation and do not develop Parkinson's. And sure enough in the biopsy of the intestine there are Lewy bodies in the neurons of the intestinal wall and there are indeed dopaminergic neurons in the intestine and these dopaminergic neurons do seem to degenerate. But there is a famous neuroanonymous called Brock who looked at lots of brains and lots of places in the brain show Lewy bodies before dopaminergic neurons show Lewy bodies, particularly those with long axons, but the other places with long axons don't seem to show symptoms. Another dramatic effect in early stage Parkinson's is sleep disorders, especially rapid eye movement sleep or REM sleep. Also patients in early stage Parkinson's seem to have trouble smelling. Later stage Parkinson's patients clearly have in many cases depression and then in the latest stages of Parkinson's there is also some dementia many times. And so Parkinson's is by no means a pure loss of dopaminergic neurons. There is a degeneration which pervades eventually the entire brain. So genetics. There are about 16 genes associated with Parkinson's disease. Together they all account for perhaps 10% of Parkinson's disease. In some societies one or another of these diseases predominate. Typically the familial Parkinson's disease occurs a bit earlier. 30s to 50s. Sergei Bryn carries one of these mutations and he has been convincing 23 and the founder of Google. He has been convincing 23andMe, which is one of these genotyping companies to get lots of genotypes from Parkinson's patients. So there are various proteins involved that contribute to, that are very highly associated with Parkinson's. The pattern of inheritance is different. Autosomal dominant means that one copy of the gene will cause the disease. Autosomal recessive means that one needs to have two. And more is known about the early ones than the later ones. Certainly the most famous of the genes are alpha synuclein and parkin. Alpha synuclein is an intrinsically disordered protein that seems to be involved in membrane fusion among various organelles and probably in transmitter release in the membrane fusion associated with transmitter release. Parkin, entirely different function, it is an E3 ubiquitin ligase involved in clearing misfolded proteins or others marked for removable. So then there's LARC2, which is a kinase. LARC2 seems to be most apparent in Middle Eastern families. And so among the 10% of patients, for instance in Saudi Arabia, who have a familial Parkinson's, there's a surprisingly large number of LARC2 mutations. Any questions? So what is the pathophysiology of Parkinson's? Well, one has to say right off that most of the causes are unexplained. Dopamine-ergic neurons have this particular problem in that they make this transmitter, dopamine, with two adjacent hydroxyl groups. It is a catecholamine. This is a catechol, it's a catecholamine. And these can very easily be oxidized. And so the breakdown products of dopamine are undoubtedly a cause of Parkinson's disease. There are some very nice studies out of UCLA looking at inhabitants of the Central Valley of California and correlating increases in Parkinson's disease with the amount of pesticide spraying. And so it's thought that the pesticides become taken up into dopamine-ergic neurons and become toxic. Then there is of course the frozen addict story. This happened about 30 years ago in the Bay Area people started making a synthetic heroin using a bad formula. This was obviously illegal. This synthetic derivative of heroin was highly toxic, but was taken up by the dopamine transporter, which is expressed only in dopamine-ergic neurons and is the target for many drugs of abuse and of therapy including ADD medications. So this toxin taken up by the, this pro toxin taken up by the dopamine transporter was converted into a toxin in the dopamine-ergic neurons and killed virtually all of the dopamine-ergic neurons. Another death of dopamine-ergic neurons occurred during the worldwide encephalitis pandemic of 1918. And some of the people in this pandemic, pandemic means epidemic all over the world, had selective death presumably because of autoimmune reactions to their dopamine-ergic neurons. And when the late Oliver Sacks was still a medical student, he spent some time in a hospital, so this was in the late 60s, mid 60s in New York, found many patients who still had virtually complete paralysis due to this loss of dopamine-ergic neurons. And at the time, Eldopa was just beginning to be approved and his first book, Awakenings, was about the patients who transiently were remarkably benefited by Eldopa. Okay. So, alpha-synuclein with these mutations. So, what does it do? Oh, how embarrassing. We really do not know what alpha-synuclein does, but also for Alzheimer's, one of the earliest aggregation products may be the one that is most toxic in Parkinson's disease and the Lewy body may be a very late stage of that. One of the other early factors may be improper fission and fusion of mitochondria, and David Chan here at Caltech is one of the experts on that topic. Okay. So, what about these protein folding problems? I'm reproducing here a figure from Candel, but much larger so that you can see some of the topics. So, one of the neurodegenerative diseases is an expanded triplet repeat. We're not going to talk about that. Another is a missense mutation in a gene. We've seen these examples in Parkinson's and earlier today in Alzheimer's. ALS we are not going to discuss at all, just no time, but in general, it is thought that the protein that's made has an incorrect confirmation, and this incorrect confirmation persists and can't be cleared from the cell and may engage in incorrect protein-protein interactions or protein-nucleic acid interactions. In some cases, the cell can mount a defense bringing in chaperones, the unfolded protein response, the ubiquitin proteasome system. But in many cases, because this misfolded protein persists, it goes on for a long time, ultimately the misfolded protein begins to alter gene expression, alter mitochondrial function, alter synapses, begins to induce apoptosis and also causes inflammation. Axonal transport is a very delicate function of neurons, especially of neurons with long axons, and so this can easily be deranged, and so the picture in Candel shows in the late stages of a neurodegenerative disease obvious morphological changes and eventually cell death. We'll come back to this picture in a few minutes when we discuss nicotine. There are animal models for Parkinson's among the favorite animal models are mice treated with toxins, I think we will talk about that, but Drosophila that over-express various proteins that are associated with human Parkinson's disease are also fruitful and handy. There are a few dopamine-nergic neurons in Drosophila and when one over-expresses synuclein in these dopamine-nergic neurons, these dopamine-nergic neurons die preferentially. Other neurons do not, but the dopamine-nergic neurons do, and in fact these mice, sorry, these Drosophila have a kind of movement disorder. Normal Drosophila can climb very well, but Drosophila over-expressing certain synuclein mutants show a much poorer climbing ability, and Professor Bruce Hay here at Caltech has studied this along with Professor Yao at UCLA. Good. Ming-Gao, sorry. Okay, more models for Parkinson's disease, toxin-treated mice, rats, and monkeys, in which there are insults to these delicate dopamine-nergic neurons, mites with altered specific genes, even more reduced models, yeast that have synuclein mutations. The current emphasis on human embryonic stem cells and on induced pluripotent stem cells have given rise to the idea that you could do a disease in a dish. You could take a human neuron, a human stem cell, differentiate it to become a dopamine-nergic cell and ask the consequences of that, especially of a mutant, that you can either induce or find in a patient for the function of that cell. There are some technical issues associated with making embryonic stem cells. As we pointed out, there is the handlebar in the upper lip. These are two different types of dopamine-nergic neurons. The handlebars degenerate. The upper lip does not. The handlebars are the substantia nigra pars compacta. The upper lip is the ventral tegmental area, and we don't yet know how to differentiate neurons into the one or the other. Biomarkers. Again, there is probably the experienced neurologist. Carries the day. There is no blood test. The best indication of early stage Parkinson's is responsiveness to L-dopa. We'll talk about L-dopa in a while. Then there is also an imaging drug. It is a high-affinity dopamine transporter ligand. When dopamine-nergic neurons die, the dopamine transporter dies with them. There are lots of movement disorders, essential tremor, et cetera. A good neurologist can tell them apart, but imaging of dopamine-nergic neurons can also help. As usual, one gives a mealy-mouth statement about confirmatory tests, monitoring disease progression. That's probably a good use. Heterozygote advantage, non-known therapeutic approaches. The therapeutic approach that is most commonly used now is L-dopa. L-dopa is a precursor to dopamine. However, dopamine does not cross the blood-brain barrier. L-dopa does cross the blood-brain barrier. It is a Twitter ion. It's uncharged. Here, it's an amino acid. It permeates into the brain probably via a transporter in peripheral tissue. Now, there are also enzymes in tissue that will catabolize, will break down L-dopa. It's also used with a compound called carbidopa, which inhibits the d-carboxylase that would otherwise break down L-dopa before it gets to the brain. Sometimes people add a D2 receptor agonist. Remember, dopamine receptors are D1, D2. The D2 receptor has a rather higher affinity, so you can increase it with a D2 receptor agonist. We'll talk about dyskinesias in a moment. Obviously, L-dopa is effective only as long as you have dopamine-ergic neurons in the patient. These dopamine-ergic neurons can take up and secrete dopamine. When those dopamine-ergic neurons become too few, then the L-dopa starts not working very well. There are other reasons why L-dopa is not a great drug. There are side effects which are called dyskinesias, literally bad movements. They are very common in people who have used L-dopa for many years. In fact, most of the Parkinson's patients that one sees have the L-dopa-induced dyskinesias writhing in quick movements. You can see TV appearances of medicated Parkinson's patients who do that. Why and how L-dopa causes these dyskinesias is not known. I have a theory, but most people think of other reasons. Other effects of the L-dopa are poor sleep, hallucinations, in some cases psychotic symptoms, although that often comes from the D2 agonist. Very simple confusion. One of the remarkable aspects of this dyskinesias is that there is an on and off phenomenon. People go from having the dyskinesias to not having them during the course of the day. Really, they occur even after a person has stopped taking the L-dopa. This is really a mystery. Other drugs, monoamine oxidase inhibitors, maybe to stop production of toxin, muscarinic antagonists. These were actually the first drugs used for Parkinson's. A mantidine, which blocks NMDA receptors like memantine, maybe this reduces excited toxicity, mitochondrial stabilizers, and adenosine receptor antagonists. We don't understand how they work, but they seem to give a little bit of symptomatic relief. Deep brain stimulation for Parkinson's. I'm going to go over by about five minutes today. There's this feedback loop involving the positive and the negative projections in the basal ganglia. It has been thought for a while, let's interrupt the feedback loop. In fact, a favorite way to interrupt the feedback loop originally was to lesion one of the nuclei in the basal ganglia called the globus pallidus, parsexterna. Just destroy it. In order to make sure that people were lesioning correctly, they put electrodes on their wires that they were going to use to pass a lot of current, and recorded from neurons, and then stimulated those neurons to make sure that they were getting to the right place. And, lo and behold, it turned out, of course, that simply stimulating neurons in the right place, not lesioning neurons, also quieted down the tremors of Parkinson's disease. And so that's where deep brain stimulation came to the fore. It's been around now for almost 20 years, and it obviously involves an invasive surgery. You have to put wands with electrodes deep inside the brain. And so the question is, how does deep brain stimulation work? Does it work by activating neurons? By silencing them? And many people think that silencing is the answer because the stimulation frequencies that work are around 160 Hz, too frequent to silence neurons reliably, possibly enough to depolarize them, and therefore inactivate them. And the other possibility is that actually they're not working on the neurons themselves, but on the axons passing through. Deep brain stimulation is remarkably effective. I'm going to show you a video. Okay, thank you. That comes from a German clinic. Probably almost 20 years old. Okay, so they're all just starting the patient to open and close for this patient to have a deep brain stimulation.  Okay, now open it up. She can do that as well as she can. Okay, and with the other hand. Now the other hand, please. She can do that a little bit. Yeah, exactly. Okay, get up. What are we going to do? I don't know. I don't know. Okay. Okay, try to stand up again. Stimulator is there. It's got a magnetic switch, but it's locked. And now you're going to try to put it back here. It doesn't work. Not even if I hold it. It doesn't work either. Try it again. I already have it. Slowly with support from the neurologist, she is working. So now, a few moments. The neurologist is going to turn on the deep brain stimulation. Maybe you'll have to be a little bit more careful before you do that. The side is changing. So, don't tell me. I've got it. Then let's go back to bed. Slowly bringing her back to her chair. Okay. Now you're using the magnetic emulation. Can you do it, Markus? Yes. And then she's got bilateral stimulation. Now it's easier to do the same kind of stimulation. Open up as far as possible and back together. And go as fast as you can. But always open up completely. Always open up completely. And then with the left hand, please. Open up completely and close up again. And then with the right hand, open up completely and close up again. Always open up completely and close up again.  And stand up. And then come down. And then come down. Then you can go back to bed. So, the question is whether deep brain stimulation for Parkinson's actually delays degeneration? There are a couple of papers suggesting that it does. Professor Viviana Grosjean has said that it's a very important thing to do. And so, the question is whether deep brain stimulation for Parkinson's actually delays degeneration? There are a couple of papers suggesting that it does. Professor Viviana Gradi-Naro here at Caltech is very interested in that topic. And she also has one of the early papers, one of the very key papers on optogenetic stimulation as a substitute for deep brain stimulation in a mouse model for Parkinson's. Now, smokers get less Parkinson's disease. More precisely, in retrospective epidemiological studies, there's an inverse correlation between a person's history of smoking and his history of Parkinson's disease. More than 50 clinical studies show this over a period of 50 years. So, the question is, is this causality? Does tobacco use to protect against Parkinson's? Or is it inverse causality? Do Parkinson's patients use less tobacco? Now, remember that the handlebar moustache, there's the substantia nigra movement degenerates. And the DTA, the upper lip pleasure, both activated by nicotine. In humans, there's a little bit of a crossover between these two organs. And so, it's possible that the substantia nigra encodes some pleasure. So, when the substantia nigra degenerates, stops producing dopamine in response to nicotine, maybe patients stop smoking, they certainly do. Maybe that's enough to cause the inverse correlation, which has also been ascribed to causality. But animal models show that nicotine itself probably is part of the neuroprotective action because you can do lesions of rodents and monkeys, and nicotine protects. And this protection in a sort of a hokey paper, alpha-4 nicotinic receptor knockouts don't have this protection. So, we need additional data, and one of the best bodies of data are going to come eventually from studying the hundreds of millions of people in the world who take up vaping. And so, we will ask whether vapors get less Parkinson's disease. At least we'll know it's nicotine. How about using nicotine patches? Nicotine itself, and in fact, there is a clinical trial underway for Parkinson's patients given nicotine patches. I claim that clinical trial is poorly conceived. Nicotine itself is a very good addictive drug, but it's not a very good therapeutic drug because it affects lots of different nicotinic receptors and because many people can't tolerate nicotine. Drug companies know this. They're trying to make nicotine derivatives. So, what is the basis for nicotine's protection? How can it addict the upper lip but protect the handlebars? We have a paper impressing the Journal of Neuroscience suggesting that nicotine enhances the cellular defense pathway. Early on, so that cells are better able to protect themselves against certain misfolded proteins and never get into the apoptotic arms of the pathway. We'll see whether that pans out. Other therapeutic approaches, limiting neurotrophic hypothesis you may remember well. And so, the question is whether you can give neurons the right kind of growth factor to protect them and the right kind of growth factor is GDNF, GLEAL-derived neurotrophic factor. Unfortunately, trials with GDNF failed. They were tried at AMGEN first 25 years ago and they did not work. And so, then the question is what about gene therapy? To put in cells that release GDNF, there are some encouraging trials underway now. Let's see if that works. And then, there are other gene therapy approaches that actually convert the subthalamic nucleus, one of the excitatory nuclei, to be more negative, which ought to interrupt that feedback loop and those tremors. And those trials are underway now by using an adeno-associated virus to make these guys inhibitory. Lots of stories to tell. I can't be unfortunately at office hours today and I will not be here next week, but if you want to know more, email me. And have a good weekend and a happy Thanksgiving.


In the previous section, we saw how each of us may have a very different view of the world even when we are looking at the same thing. This raises a pertinent question for us as researchers, which of these views is more valid or real? What is reality and whose reality is more real are questions that are particularly important to our work as ethnographers. Because ethnography is a research method that emphasizes on engaging with and learning from the real world. So, when we observe reality of a context, we have to wonder is this what we are observing real? What makes us think that this is actually real and not fiction? And whose perceived reality is more real? Are or are participants? Is it possible that one person's reality can be another person's fiction? These questions indicate there is more to reality than what we perceive on the surface. It is not like what you see is what you get.  We take the world around us and its underlying forces for granted.  Structures such as social and economic hierarchies, beliefs and knowledge systems, social contracts and so on. This underlying machinery manifests in the everyday interactions, behaviors and functions that we see on the surface. It is through observing the surface that we as ethnographers try to understand the structures that lie beneath. The sociologist Emil Durkheim puts this very simply and beautifully when he says, sociality is built into structures and institutions. It is a way of saying that everyday life is governed by social structures. What is right and wrong? What is normal or extraordinary? What is moral or immoral? What is real and what is unreal? Each of this is defined as per the context it is situated in. What is ordinary in one context may be completely bizarre or strange in another. The institutions and structures that we see around us such as marriage, family, friendships and other relationships or institutions such as governments, educational institutions, offices. These are all governed by an underlying logic of social agreement and contracts defined by cultural context in which each of them operates. But not everybody has the same beliefs. Reality is not one reality. In fact, realities are constructed. Let us consider an educational institute. If a building is designated as an educational institute, the way it functions will be defined by the characteristics that we as a society associate with the idea of an educational institute. We designate it as a place where people go to learn and to teach and to administer other related functions. If for whatever reason students stop going to classes or teachers stop teaching or the institution lost its funding, then it will stop being an educational institute. It will become just a building or at most a building that used to be an educational institute. The reality of the building will change not because its structure or shape has changed but because as a collective we no longer assign the same value or characteristics to it as we did earlier. What so far was the obvious reality of the building will no longer be the same. Therefore, our worlds are really made up and defined by a set of social agreements of the ways in which to interact and function but also of commonly agreed upon beliefs and knowledge. A really interesting example of this is the idea of money. All of us use money in pretty much the same set of ways. Earning, spending, saving, donating and so on. We base a lot of our life's functions and even desires on the amount of money we have or hope to have. But if you stop and think about it, what is money? It is an idea, a medium through which we can compare cotton to gold or equate the time and effort of a person to some material tangible objects like a set of bank notes. Looking at the idea of money in this manner, we realize that as a society we have come to a shared understanding of giving value to things so that we can compare them to each other. Otherwise, can we really compare time and effort to pieces of paper? Are there really any attributes that can be used to compare gold to cotton? But we have all agreed to the idea of particular pieces of paper or metal or plastic minted in particular factories and signed by a particular authority as the physical manifestations of this value. Let us pause the video here and ask ourselves this question. What is the value and meaning of a debit card to someone who uses an ATM regularly and to someone who does not for example a young child? Think carefully and justify your responses. Some of you may have said the value and meaning of a debit or credit card is the same for all people. And some of you may have answered that the meaning of the card remains the same but different people associate different values with it. Let us discuss the question some more. Imagine what happens when we lose our wallet with our money and our bank cards in it. For many of us, the first step of action is to call the bank hotlines and block our cards. This is because the cards are the access points to our bank accounts and all the money in them. Now imagine that this wallet and the cards in it are found by a young child. If the child has no experience of using debit or credit cards or even an idea of what they are, she won't attach any value to them. She may throw them away or stash them in her toy basket. In either case, she will not give these pieces of plastic the same kind of importance as someone who is aware of their usage. This shows that even when we agree almost universally on an idea such as the idea of money, the values and meanings attached to it are far from universal. Each person, each group has their own reality which transforms as circumstances and situations change. Each person's reality shapes the world that they live in. What they define as valuable, relevant and meaningful is a function of the reality they inhabit. This is a complex idea but an important one. Let us discuss this in detail in our next section.


Hi, everyone. My name is Tal Oppenheimer. I'm a product manager on the Chrome team. And I'm here to talk to you about how you can use all the technologies that we've learned about today to make sure that your experiences can work for billions of users. So when we're talking about billions of users, that's a pretty big number. And that means that we really need to think about how can we reach all of our possible users. And one of the really critical things here is to figure out who your users are and to actually understand how they'll be accessing your experience and what this means. Now for a lot of us, we spend a lot of time thinking about what product problem we're trying to solve and who we sort of have this mental image in our head of who our user might be. And for many of us, this can look a lot like us based on just what you're used to and the experiences that you've had. And this can lead to a perception of the world that looks something like this. And now we are in Amsterdam, so a few of us might be thinking a little bit outside of the United States. And you can throw sort of Europe in there as well. But this isn't the whole world by any means. And it's definitely not your user base when you're thinking about all of the internet users. So today, there are roughly 3.3 billion users using the internet around the world. And if we actually drill down and look at where these users are, this is a map of internet users today by country. And you'll see that while there are some users in the United States and some in Europe, we see much more pronounced number of users in a lot of these other areas. So while the US has about 286 million internet users, India has 462 million internet users, and China actually has almost as much as the two of these combined with around 721 million internet users. But what's really striking here is not just where the internet users are today, but looking at where the growth is coming from. So if you look at a snapshot over the last year, you'll see that in the last year, a lot of internet users came online in one very specific country. And this is India. So we saw over the last year that 108 million users came online in India alone. And for India, this was actually a growth of 30% year over year compared to the number of users that they had before. And this growth was 10 times more than the growth we saw in China in terms of absolute users. And over 100 times more, the growth we saw in any other country over the last year. And just to put this in context, this growth in India in a single year was equal to one third of the United States' entire population. And that's just in one year. And what's more is actually if we look at who's not yet online, and where we sort of predict that the growth will be coming from, we see the shift away from the United States and Europe to other countries. So in India, you still have 864 million users not yet online. The current user base, there's still 65% of India's entire population not online. Or over 20 times the number that's not yet online in the United States or similar areas. And so this sort of question can come up, how do we reach these users? If we need to be sure that we're building for all of them and thinking about all of them. And as I mentioned before, what's really critical here is to understand your users and understand who they are. So I know we've been sitting for a little while, but just with a quick show of hands, how many of you remember the first time that you accessed the internet? Okay, looks like most of us do.  Okay, we've got no hands up at this point. So most of us probably accessed the internet for the first time on a desktop machine or maybe a laptop. But when I was in India last year, we spent a whole lot of time talking to internet users who maybe knew where to the internet or had been using it for a fair amount of time. And I was sitting down with a woman who was sort of in her mid-40s, we were sitting in her living room and I asked her the same question. If she remembered when she accessed the internet for the first time and what device she used to access it. And her answer was yes. She did remember the first time she used the internet. It had been earlier that year. She borrowed her husband's cell phone and accessed the internet for the very first time. A few months later, she got her own cell phone and was now able to regularly access the internet. And so what this means is that how people are coming to your experience and interacting with it is just fundamentally different. We've heard the mantra mobile first probably a number of times. And for us this often means thinking about design mobile first, thinking about how our experience would work on a mobile phone. But for a lot of these users, how they're actually accessing with the internet, isn't necessarily mobile first. It's actually mobile only. They haven't had an experience on a desktop or a laptop computer. And they may not be using one regularly and they may not even in the coming years be using one regularly. So in terms of how they'll be interacting with your experience, it is only gonna be on that mobile phone. And so this means that you really need to think about what your experience can be like for users who may not have had experience interacting with your product on other platforms and making sure that you're still designing for that in mind. But beyond just the sort of using mobile first, this means that it's also really important for us to think about what the device that users are using are like. So taking a look at one device, this is a device that some of us might have in our pocket. This is the Nexus 6P and it was released in 2015. So last year, it's a pretty big device, 5.7 inches measured diagonally, and has three gigabytes of RAM. And then depending on how much you wanna buy and how much you feel you need, it can have either 32 to 128 gigabytes of storage. Now in comparison, when we were in India, we went to a number of stores and actually asked the shopkeepers, what device do you sell? What device do people ask for? What would you recommend for me? And this is just an example of one device. This is a Samsung J1. And this device was also released in 2015. It's 4.3 inches measured diagonally, so a bit smaller. It has 512 megabytes of RAM and 4 gigabytes of storage. So these are two devices that were released in the same year but have very different specs. We see one sixth of the RAM and even in the best case scenario, one eighth of the storage capacity. And this means that the user is gonna be accessing your experience on their mobile phone under a very different context than the phone you might have in your pocket and the phone that you might be testing on and seeing what your experience looks like. And now the difference in context goes beyond just the physical form factor of the device that they're using. Because they're relying on cell phones, this also means that cellular connection is their primary way of accessing the internet fairly often. Now, many of us are probably used to accessing Wi-Fi, we've connected to Wi-Fi here, probably sometimes complaining about its speed. This isn't necessarily the case for the users. And it's because you're relying on something that's in your pocket, as you move and shift scenarios, so does your connection to the internet. And you need to keep this in mind when you're building experiences. But this phenomenon is happening all over the world, we also see that in the United States, 20% of US households rely only on cellular data when they're making connections to the internet. And what's really interesting is that this number's actually doubled since 2013. So we're seeing this increasing. So the reliance on cellular networks as your primary way of interacting with the internet is increasing across the globe. And this has some consequences when you're thinking about the conditions that someone is trying to access your experience under. Now we've heard a lot about sort of slower connections and the impact this can have, but we see that globally, about 60% of mobile connections are 2G. And this is just actual 2G connections. It's not necessarily talking about 2G-like speeds, which can actually be even larger. And when we start thinking about the areas where people are coming online for the first time, we see this more pronounced at about two thirds of the connections. But what's more is that, while we're seeing this decreasing, we're not seeing this decreasing at a very fast rate. The predictions, if you sort of estimate it out, is that by 2020, one-fifth of the connections globally will still be 2G. And again, this is still excluding those 2G-like speeds. So the problem of connection speed is gonna persist for the foreseeable future. And we've seen some stats about this before, and it's sort of widely accepted that a delay in your experience has a very large impact on how users experience your site. And we've seen that a study found that one single second delay in your page load time can lead to 11% fewer page views or a 16% decrease in customer satisfaction if we're talking more qualitatively. And so that 2G connection that might have very slow round trip times, if that impacts what your experience is like for the user, is likely to have a very negative impact on how happy they are with what you've built. But beyond just the connection quality that is introduced by users relying very often on cellular connections, cost also starts to play more of a role here. So looking at India again, and doing an estimate of sort of minimum wage, minimum wage in India is a little bit complex as it depends on your job role, et cetera, and looking at how expensive a data plan is. With some simplifications, we see here that on average, you would require 17 hours of minimum wage work in India to purchase a 500 megabyte data plan. And we're all, we've been thinking about the mobile web, so just to put this in context, looking at sort of the average size of a web page today, if a user in India receiving minimum wage were to spend that entire paycheck on just data, just to access the mobile web, one hour of minimum wage work would load about 15 web pages. And just take a moment to think about how many web pages you've visited today or even visited during the last talk or during this talk, and think about how many hours you would have had to spend to be able to afford that. And what this really means is that the cost of data requires a trade-off. If they use one thing, it means that they're not using something else. And they're constantly making these trade-offs to make sure that the data that they have is used in the best way possible. And this results in the frequency of their connectivity really varying. When data costs are so high, you need to make a choice if you're gonna use one thing or the other, and sometimes you just wanna turn it off altogether. One user that we spoke to actually said that on an average day, they turn airplane mode on and off 12 to 15 times, because when you're not using your phone and you put it to the side, if data's this expensive, you wanna make sure it's not getting used unless you find value out of it. And this means that if you're trying to get a user to interact with your experience, you really need to make it worth it for them, because they need to be willing to pay that amount to just access that experience. And so this might be a little bit daunting, right? These are a lot of different constraints and conditions under which people are accessing the internet that you may not be familiar with firsthand. And so you may be posing the question, great, people are using mobile-only devices, connections can be intermittent, they can be slow, and when they do exist, they're really expensive. So what can I sort of do, and what does this mean for how I develop? So some of the methods that we think about might be a little bit hard. Under some of these conditions, installs become really challenging, because what you need to do here is convince a user to pay the time and data costs to install your experience before they've even tried it out. And this can be really hard when the costs are so high and the networks are slow, because it can take sometimes hours to download a single app. And what's more, if the device has limited storage capacity, your APK size starts to be really, really important. You need to start to make sure that it's small so that a user doesn't have to delete photos or videos or other apps on their phone to make space for your experience. And what's more is even beyond this first step, you're probably working to improve your experience, which probably means you want your user to update their app, and this is, again, once again challenging because they need to take that extra step on that slow connection or expensive connection. But you're all here. You probably all know that there's an app that solves a whole lot of this. The mobile web, as we know, solves a lot of these things just inherently and how users interact with it. With the mobile web, as soon as they navigate to your experience, they see your experience. They don't have to take an extra step before they try it out. They got there, they see it, they can try it out. This also means that storage constraints for that initial interaction are non-existent. Just by virtue of finding it, they can see it and start using it. And it's always up to date, so as you continue to make improvements on your product, your users get them right out of the gate, and they don't have to go take an extra step just to see the latest and greatest that you've built. But as you know, we've been talking a lot about the reach that this introduces. And what we've seen, these are some stats that we talked about last year, is that removing these barriers has a real impact on the reach that your experience can have. We see that on average, users navigate past 25 apps per month, and this is compared to over 100 websites that a user will navigate past on Chrome on Android in a single month. And this not only is a breadth of experiences that users pass by, but has a real impact on the number of users that a single experience has. So looking at the top 1,000 mobile apps and the top 1,000 web websites, we see that on average, there is 2.5 times as many users on the mobile web as there is on these top 1,000 mobile apps. And what we're seeing is that mobile web is also growing at two times the rate of native apps in terms of numbers of users in these same buckets of top 1,000. So really what this means is that the web inherently provides you a whole lot of reach. And we've been talking a lot about today is how you can use progressive web apps to not only leverage the reach that the web inherently has, but to build experiences that really work well for you and for your users so that they highlight and have all the capabilities that you need to build the best possible experience and for your users to get the best possible experience. So I'm not going to focus on this too much because you've heard a lot of this today, but progressive web apps overall not only offer a very smooth experience, but they also offer a lot of options for how to support some of these other situations that you really need to think about when you're building for billions of users. So how can you leverage progressive web apps to actually reach and build great experiences for users around the world? So the first is cost. We talked about how cost can be very limiting for users to even try out your experience for the first time. So we'll talk about how you can leverage progressive web apps to really remove that barrier. And second is connectivity. When you do interact with these sort of flaky connections, how can you address that to make sure your experience is still as fast as possible? So you're not incurring that one second delay that has a huge impact on users' experience. And finally, how can you make sure that you're making the experience as simple as possible and just removing as many extra steps that your users may or may not need to actually take so that things continue to be fast and efficient? So to jump into the first one, cost. Now on Chrome, we've been working on addressing this issue across the board. So we do have a Chrome data saver. This is a proxy for HTTP content that a user can turn on. And with functionally no fidelity change, users can see up to 60% data savings. But we've taken this a step further because we know that cost can be very constraining for some of our users. And we've actually decided that on slow connections for HTTP content, we will automatically replace most images on the pages with placeholders. We maintain things like navigation icons, et cetera, so users can continue to load the page. But at this point, the user's in control of where their data goes. So they can choose to load all the images on the page. They can long press on a single image to load it if they need it. But we're not using their data without their knowledge and without them needing it. And we've seen that we were able to increase data savings to over 70% in some of these situations. But we also know that this doesn't necessarily work for all experiences. And so there's also a number of client hints that you as a developer can use to make sure that you're optimizing the experience for the users based on the device that they do have. So with DPR Width and Viewport Width, you can make sure that you're only sending the image size that you need to the users and so that they're not incurring data costs for something they may not be using or may not actually need. What's more is we've also launched a save data header. And in Chrome, this maps directly to whether the user has that data saver had feature turned on or not, which means that you as a developer know which users are the most data sensitive and can adapt your experience accordingly and can do so in the way that works best for your product. So maybe that means only loading one key image that's critical for it and making the other one sort of on demand for the user or not auto-playing video or whatever it might be that makes sure that you aren't removing constraints for the users who need it most while still making sure that your experience works for them. But we also know that this can be challenging and there's a lot of optimizations to go on. So we also have the PageSpeed module, which is a server side component that you can actually drop into your web server that will do a lot of these optimizations for you. And if you drop this in this, it can do the optimizations on both HTTP and HTTPS content with functionally no fidelity change. So it's similar to that data saver feature that we have on Chrome overall, but you can do it on all types of content. And what we've also done is we've actually gone a step further so that for the users who have data saver on, we do a few extra optimizations to make sure that we're really doing as much as possible to help those users who are feeling sort of most constrained or who have expressed interest in us saving them even more data. So just to give an example of this, this is an example of a Monk storefront that we built. On the left, you'll see a screenshot of the store with no PageSpeed. And on the right, you'll see it with PageSpeed. Now these look really familiar and very similar. If anyone can point out any differences, let me know afterwards, but they look functionally identical. But there are actually differences when you dig into this. So if you look at the one on the left here, this is 350 kilobyte paid. So it's relatively lightweight compared to the sort of the average website across the board. But simulating a 2G connection, this page can take over a minute to load. And as we know, waiting is bad. It causes a bad user experience. It causes your metrics to hurt. And you really want to reduce that as much as possible. Now by just having the optimized for bandwidth in PageSpeed module, what we see is that we are able to actually shrink this to 165 kilobytes or about 50% fewer bytes. But for users who have data saver on and we go even further, we're actually able to shrink this to 120 kilobytes. And what's more is on the same simulated 2G connection, we actually drop the load time to under 30 seconds. And this is functionally with no fidelity change to the user. The user is seeing the same thing, but you are saving them data and saving them time just by dropping this one line of code in. And what we're seeing is this is just one example, but we've seen that on average, even for users who do not have data saver on, we see about 37% data saving with no fidelity change at all. But beyond just removing cost and decreasing cost that comes with data usage on mobile, in connectivity is really important and you need to make sure that things load as quickly as possible. So just to give a sense of how these things can vary based on connection types. So round-trip time or the time between making a request and actually getting a response varies pretty drastically between all these connection types. At one extreme, you often see sort of 50 milliseconds, round-trip times on Wi-Fi, I know conferences can be different, but at the other extreme, you have sort of 50 times slower on an average 2G network with 2,500 milliseconds round-trip times. And so this can be a little bit daunting, what can you actually do about this? So the first thing you can do is downlink Max actually offers you a way to know which connection type in the first place your user is actually on when they're accessing your experience. And you can subscribe to updates. So if a user switches connection types, you as a developer know and can make sure that you're giving them the best possible experience and not incurring any of those delays that might otherwise happen.  So we've heard a lot about Service Worker today, right? We know it's a client-side proxy and written in JavaScript and you can use it to support offline and all these things. But you can also use it to make sure that your experience is as past as possible. So Jake this morning talked about Wi-Fi or the experience where your phone thinks it's connected, but you as a user are not actually getting anything and this can be incredibly frustrating. This isn't only those sort of really flaky intermittent connections, but this can also be the case when you're on a really, really slow connection and the round-trip times are just so large. And so what you can do here is with Service Worker, you can actually implement request time-outs to address these flaky connections so that if a user is on that really slow connection, they're still getting something very, very quickly and they're not waiting for it to load. But we do know that sometimes there's no connection, right, we've seen this offline down to a lot today when we've been talking about Service Worker and we're really trying to make sure that you all have all the tools you need to kill the offline dyno and make sure that when a user goes to your experience, they're never gonna see this offline dinosaur. But there's been a lot of interesting ways that we've seen people who have been leveraging progressive web apps address the offline situation in a way that addresses the flows that are most critical to them. So just as one example, this is Conga. Conga is one of the top e-commerce sites in Africa and they will actually be talking a lot more detail about their progressive web app tomorrow. And what they've done is they've built a checkout flow that can work completely offline. So for users online and add some things to their cart and then loses connectivity or goes offline or turns on airplane mode for whatever reason it might be, they've actually adjusted their flow so that instead of having an online checkout flow, it has sort of a call to order flow so that the user can still complete the transaction or the flow that's most critical for their product in a way that works regardless of their connectivity type. So they've really taken their time to think through what is the critical use case for our users and how can we actually let them complete that use case even if they have no connection. And what's more, they've actually found that for that critical flow, this has shown a lot of improvement. So compared to their previous mobile website, this used 84% less data. And so addressing a lot of these speed connect issues also has a benefit of addressing some of those cost issues that we talked about earlier. What's even more is that compared to their native app, this new flow actually used 82% less data. So this has been a drastic improvement, not only to their previous mobile website but also to their native app experience. And again, they'll be talking a lot more about their overall work tomorrow morning, so feel free to come to that. But beyond just trying to address connectivity and cost, removing complexity is always a good thing. Making things easier is always just gonna be better for your users. And when we're talking about users that are sort of coming online for the first time, every step you're asking your user to take is time and money because on those 2G connections, every page load is just gonna be sometimes minutes of waiting. So if you're giving them a page load, you need to make sure that page load provides value. And if it doesn't, get rid of that step. And there's a few ways that we can make that happen. So we've talked a lot about add to home screen and how you can use this as an easy way for users to get back to your experience. This can also be used as an easy way to cut out steps for your user so that users who are more engaged and have expressed interest in your site can with one tap get right into your site. They don't have to take extra navigations, wait those five, 10 minutes, spend that data on those page loads just to get to your experience. They can tap on it straight from their home screen. But beyond that, with the notifications, you can also make sure to deep link them to specifically the part of your experience at the most critical times so that they're not taking extra steps even within your product experience to get to the part that might be most relevant to them. So this means that regardless of what their connection is or their cost is, you've just removed steps and they don't have to wait that extra time unless it provides value to them. But one of the things we talked about is that it can be really hard to try this out and make sure you understand what it's like. And so there are a few tools you can use to actually test this experience directly and make sure you're testing it with a global perspective and under all of these different situations that maybe aren't what you have in your pocket or what you use on a daily basis. So we do have a mini mobile device lab and it's up on GitHub and so this will let you simulate a bunch of different devices so you don't have to go out and buy a million and a half devices, but you can make sure you're simulating your experience on all of these different devices to see what users who use devices that are very different for yours are actually experiencing. But what's more is you can actually use DevTools to understand the cost of your experience. So just to walk you through one thing here, so we've talked a lot about DevTools but I wanna call your attention to the network piece specifically and so you'll see a button at the bottom here that actually lets you know what the payload of your load was. And so right now it's started sort of pretty light, 785. If we look a little bit more into this we notice a lot of things came from cash so probably why it was pretty light but you can actually just go ahead and hit refresh here and now you'll see that sort of on a fresh load this was actually quite a bit heavier and so it was over 200 kilobytes and so this is just one example but you can use this as you're navigating through your experience to get a sense of like, okay, how many megabytes is a user using if they're actually actively using my experience? But going beyond this, you can also use this to understand the time and how much time users are spending on just waiting for your page to load. So you'll see the time down here right next to the megabytes but what's more is you'll also notice that up here you can throttle it and change the simulated network speed so that you're not relying just on your wifi to see how the page load actually happens. So if you'll see that if we change this to 2G this actually starts going from 600 milliseconds that we saw before to roughly 11 seconds for just this page to load. And what you can do is as you adapt your experience as you use service worker and now these other technologies that we've talked about you can see how this changes and make sure that you're really optimizing for experiences and that you're building an experience that you would be happy to use if you were actually facing sort of some of these other conditions that you might not have firsthand experience with. So the main idea here is that by keeping sort of three principles in mind you can make sure that the experience you're building not only leverages the reach of the web but also takes advantage of progressive web app technologies to build the best possible experience for your users across the board. And we have a lot of different technologies and details about how you can apply these not only for progressive web apps but specifically to address the needs of billions of users online. So feel free to go there for more details. But the big takeaway here is that just by keeping in mind the fact that not all users who are using your experience look like you and are accessing the experience under similar constraints you can do a whole lot to make your experience much more accessible and as a result have a much larger reach and have the potential to reach billions of users. And so with all of this you can really build an experience that is built to work well for everyone.  Thank you very much. Thank you.


Leah Kedlow came from Wayne State University and she presented a synthetic talk about American consumerism and she used advertisements. And what made her use of the advertisements so effective is that she used them both in her synthetic talk and then she came back to them when we got to what we usually include in all of our programs, which is a skills section, some sort of interpreting history. So she went from the general, this kind of broad approach to something that was based in research and the teachers really liked that combination. So Leah did a brilliant job at what I thought of bringing those materials together. We had other speakers who have done the same thing, Andrew Hurley has done similar work for us around his book, but he does a wonderful job of drawing a synthetic portrait and using images and other materials in it and then coming back to them and during the skills sorts of sections of our workshop. Yeah, that's and in fact with Andrew Hurley's work on consumerism, we include a tour of the suburbs of Cleveland that we've developed to compliment it, to kind of build out some of the themes he pulls out in his study of the landscape.


Welcome back agent nation. My name of course you guys know me. My name is agent beam star. Let's get Into the news ladies and gentlemen before we get into any kind of news I need you guys.   So I woke up. I'm supposed to go to 2k event What's so funny man, I woke up supposed to go to this event boom looking for my passport Where is my passport can't find my passport? I missed the flight and the whole event man's was chilling in the Hollywood Hills Playing 2k 19 early with all the content creators and I was supposed to be there and I missed it I'm mad. I sent Ronnie this DM. I was like my guy tried bro I just don't know where my passport is. I'm gonna have to get a new one So to all the people that saw that photo that cash put up and said 2k fire He said something like that and he looked where is agent? I was in Toronto miserable throwing myself a pity party eating some ice cream or something like that All right for our first story of the day ladies and gentlemen NBA 2k 19 You can choose between what kind of shop meter you want to have ladies and gentlemen You heard me correctly. You can choose between the 2k 18 shot meter or the 2k 17 shot meter now There are some differences. They're not identically the same to the way they were in those games But do you remember when Mike Wang put out the tweet and he's like guys What shot meter do you like best and then most people voted 17 16 was second and 18 was third you guys remember that pull I said in the replies to that. I was like, yo Mike Wang just make it so that we can switch between them, bro That's the best idea so you can choose between 18 17 or both Which I mean, I don't know why you'd want to have two different shot meters But I guess if you want to see as much green as possible when you're hitting your perfect releases That's that's an option for our second story of the day this one it puts a smile on my face guys because You you heard did you hear okay blow-by's and snatch bags aren't convenient to can 19 if you were if you've been abused Lemon 18 and you think you can get by 19. Uh-huh. That's over here man Now they played on the 5v5 mode So if you're playing pram or park or even my team We're not entirely clear as to whether those animations exist in those modes So if you played 2k 18 the blow-by's and snatch bags are ridiculous on program They're less prevalent, but still ridiculous on part, right? So the sliders do make a difference when it comes to that kind of stuff So I'm hoping man cross my fingers that is not gonna make a return those other modes that I love to play for our next Story of the day defense is better in NBA 2k 19 fear glissie was putting out some tweets also annoying TV Streamed the gameplay onto it, which I was like wow the first time we get a chance to see 5v5 gameplay is A couple months before the game's launch and is from content creators usually 2k is like nah We'd like to come out with the first gameplay ourselves But I guess 2k maybe got tired of people leaking with horrible quality cameras in games calm with their little flip phone And they just kind of let people upload it and so plenty people did Lsk uploaded some footage just to upload some footage cash up for upload it some footage So I'll leave cash as link in the description because he probably had the clear smoke hot my high definition Gameplay that I've seen of all the people that went to the event and you're looking at some on the screen right now as well There's no way that shouldn't have went in All the links to the stuff I'm talking about are in the description Annoying was probably the one giving out the most information through Twitter YouTube and Twitch But there's been a lot of content creators doing the same. So I got y'all. I could have been one of them, baby I could have just oh my god. I can't believe it. I cannot believe it ladies and gentlemen, I I don't know man. I'm just depressed guys gig. Hey cheer me up in the comments something like that On our next story of the day the game feels more arcadey annoying says so remember little Mike Wang for not a pool He was asking the people guys. Do you want the game to be complete simulation? complete arcade craziness or in the middle he asked people from a scale of 1 to 10 and Most people voted right down the middle. It seems like unlike 2k 18 There's gonna be a little bit more of a arcade touch tonight team Which I like it adds more of a fun factor It even adds a little bit of a skills gap because you're almost detaching yourself from realism Hey, if I'm gonna play basketball in real life, I'm walking out the door I'm heading to the gym with a basketball in hand in my duffel bag, right?  You're gonna lose the fun factors It's gonna ruin everything so I'm happy to know that like 2k 14 15 even 16 They're kind of heading back into the direction of the more fun 2k and I can only imagine if that's what they were feeling in play Now they're gonna feel it even more when they play on the park Which is why I'm excited about it for our next story of the day in one of annoying's videos He said that he was talking to Mike Wang and Mike Wang said he made shooting tougher next year And there was a bunch of posts he put up about this But I guess they're looking to actually introduce a skills gap to shooting so that the people who can time the shots the best will be the People that are more consistently hitting shots on the game annoying felt like the shooting was too hard when he was playing the demo and Him in Los Polos. He said was leaving people open, but they weren't hitting any greens He said it was very challenging to hit a green and he was talking to Mike Wang saying you might have to make the shooting Easier because if I can't hit greens, I don't even know how the casual players gonna find a way to hit greens unless of course They get incredibly lucky so when it comes to a skill gap It's pretty simple if you make shooting incredibly easy everybody's gonna be able to do it There's no skills gap But if you make it incredibly hard as to the point where even the best players can't consistently hit it Then it's gonna be too hard and there's still gonna be no skills gap There's always a sweet spot in the middle that you have to find and each game tries to find that sweet spot So Mike Wang I'm just I'm just letting you know that just because you may shooting super hard does not mean there's a skills gap I hope you've done your work to find a balance and If you did man, I'm gonna be so excited cuz you know, that's my bread and butter ladies and gentlemen This is what I do. I'm a lights out shooter. So let me find out They have a skills gap allow me some time to master said skills gap and 2k 19 Could be a whole lot of fun dropping folks off man Getting some clips and some plays that nobody's ever seen before being the first to do it. Oh, I love it I'm trying not to get excited. This is how you get let down man You take your expectations way too high So let me simmer down real quick for the next story of the day in NBA 2k 17 They announced layup meters and everyone's like what we have to time layups now But as I played 2k 17, I actually began to enjoy the layup meter It's not necessarily like a meter the way you'd shoot you just get a bonus if you release it better But you don't get anything negative by releasing it poorly in 2k 18 You still had to release your layups There was just no meter and so in 2k 19. It seems like they reintroduced the meter some people were super furious about it I'm saying well, what are you talking about? If you can't time a layup, bro Then you won't even stand a shot time and shots. So we all need to stop getting angry every single time 2k does something I'm the one saying that oh god. This is crazy There was a tweet someone sent me and he was like bro agent check this out man This was the 2k 18 shot meter. They didn't change a thing bro I'm not buying this game, and he won't like bro relax my god. Relax. We don't know the details What if they allow you to switch shop meters or something?  I want to use it So long story short give some give it time guys Let's get all the information before we begin to react which is why I'm kind of cautious about the blow-by and snatch back thing We don't know if it's in the other mode. I don't have the full information just yet So I'm staying calm for our final story of the day ankle breakers are incredibly rare in 2k 19 That's what we hear right? I also heard the same thing for 2k 18 and we can do you can hit like 16 ankle breakers in a game in that game So I don't know if things are gonna be different in the park program my team But word is that if you're a playmaker is not gonna be so easy to hit those ankle breakers Which is a good or a bad thing a good thing if you think that rarity makes it fun so that when you actually hit an ankle breaker It's worth celebrating and it's bad if you just think of it practically ankle breakers give you an opportunity to get an open bucket And if you get less of those they might have been a pretty big nerve to playmakers as a whole especially those that enjoy Isolation dribbling I don't know I am not a playmaker, so I do not care That being said that is all the information we have on NBA 2k 19 as of now Of course, there's gonna be some more leaks that come out and when they do roll I'm gonna be on it if you guys enjoyed the video drop a like subscribe if you guys are new and I'm gonna catch you Guys in the next one.


As NBA, Twitter and media and fans have been going crazy about the Lakers and their title chances. According to the odds that of course, given once again, about a number one sports book in the world, FanDuel Sportsbook, according to them, even though again, these odds do change, not much has changed when it comes to how people feel about the Lakers chances of winning a championship. They have, and I kid you not, Isaiah, the second highest odds of winning a championship still at plus five fifty behind the Brooklyn net to a plus two ten, right? So we got to think about that. So they have the second highest odds, which means they're ahead of the Clippers, they're ahead of the Jazz, they're ahead of the Bucks, they're ahead of the Sixers, they're ahead of the Suns and all these other teams. And when it comes to all right, making it out to Western Conference, the Lakers actually have the best odds still. Plus two sixty plus two sixty. So there's something to be said about the fact that again, folks, even with the struggles, even with how well everybody else has been playing, folks are still of the belief that, hey, LeBron James, A.D. postseason one game, seven games, they're rolling with them and I can't blame them.