I'm Peter Burris, welcome to another Cube Conversation from our awesome Palo Alto studios. Got a great conversation today. We're going to be talking about flash memory, other types of memory, classes of applications, future of how computing is going to be made more valuable to people and how it's going to affect us all. And to do that, we've got Scott Nelson, who's a senior vice president and GM of the memory unit at Toshiba, Memory America, and Doug Wong, who's a member of the technical staff, also at Toshiba, Memory America. Gentlemen, welcome to the Cube. Thank you, Peter. Thank you. So here's where I want to start. That when you think about where we are today in computing, in digital devices, et cetera, a lot of that has been made possible by new memory technologies. And let me explain what I mean. For a long time, storage was how we persisted data. We wrote transactions to data and we kept it there so that we could go back and review it if we wanted to. But something happened in the last dozen years or so, it happened before then, but it's really taken off where we're now using semiconductor memory, which allows us to think about how we're going to deliver data to different classes of devices, both the consumer and the enterprise. First off, what do you think about that and what's Toshiba's association with these semiconductor memories been? Why don't we start with you? So appreciate the observation and I think that you're spot on. So roughly about 35 years ago, Toshiba had the vision of a non-volatile storage device. So we brought to market, we invented NOR flash in 1984 and then later, the market wanted something that was higher density. So then we developed NAND flash technology, which was invented in 1987. So that was kind of the genesis of this whole flash revolution that's really been disruptive to the industry as we see it today. So it ended up, it didn't start off in like large data centers, it started off in kind of almost unassuming devices associated with particular classes of file. What were they? So it was very disruptive technology. So the first application for the flash technology is actually replacing audio tape and a phone answering machine. And then it evolved beyond that into replacing digital film, kept going replacing cassette tapes. And then if you look at today, it enabled the thin and light that we see with the portability of the notebooks and the laptops, the mobility of content, with our pictures, our videos and our music. And then today, the smartphone, that really wouldn't be able to, that wouldn't be without the flash technology that's necessary, that gives us all of the high density storage that we see. So Doug, this suggests a pretty expansive role of semiconductor related memory. Give us a little sense of kind of a, where is the technology today? Well, the technology today is evolving. So, you know, originally floating gate flash was the primary type of flash that we created. It's called two-dimensional planar floating gate flash. And that existed, you know, that was from the beginning all the way to maybe 2015 or so. But it was not possible to really shrink flash any further to increase the density. So that's the trend. In the 2D form. In the 2D form, exactly. So we actually had to move to a 3D technology. Now Toshiba presented the first, world's first research papers on 3D flash back in 2007. But at that time, it was not necessary to actually use 3D technology at that time. When it became difficult to increase the density of flash further, that's when we actually moved to production of our 3D flash memory, which we call Bix flash. And Bix stands for Bit Column Stacked Flash, and that's our trade name for our 3D memory. So we're now in 3D memory technology because we're creating more data and the applications are demanding more data both for customer experience and new classes of applications. So when we think about those applications, I mean Toshiba used to have to go to people and tell them how they could use this technology. And now you've got an enormous number of designers coming to you. Doug, what are some of the applications that you're anticipating, hearing about that's driving the demand for these technologies? Well, beyond the existing technology or the applications such as personal information appliances like laptops and portables, and also of course in data centers, which is actually a large part of our business as well, we also see emerging technologies as becoming eventual large users of flash memory, things like autonomous vehicles or augmented or virtual reality or even the emerging IoT infrastructure necessary to support all these portable devices. So these are technologies, or these are devices that currently aren't using the large amounts of flash, but are going to be in the future, especially as the flash memory gets more dense and less expensive. So there's an enormous range of applications on the horizon going to drive greater demand for flash, but there's some business challenges of achieving that demand. We've seen periodic challenges of supply, price, volatility. Scott, when we think about Toshiba as a leader and sustaining that kind of good flow of technology into these applications, what is Toshiba doing to continue to satisfy customer demand and sustain that leadership in this flash marketplace? So first off, as Doug had mentioned, the floating gate technology has reached its ability to scale in a meaningful way. And so the other part of that also is the limitation on the dye density. So the market demand for these applications are asking for higher density, higher performance, lower latency type of applications. And so because floating gate has reached the end of its usefulness in terms of being able to scale, that brought about the 3D. And so with the 3D, that gives us our higher density and then along with the performance that enables these applications. So from Toshiba's point, we are seeing that migration that is happening today. So the floating gate is migrating over to the 3D. It's not to say that floating gate demand will go away. There's a lot of applications that require the lower density, but certainly the higher density where you need a dye level of 256, 512 gigabit, even up to a terabit of data, that's where the 3D is going to play. And second to that is really goes into the cat-back. So obviously that requires a significant amount of cat-backs not only on the development, but also in terms of capacity. And that of course is very important to our customers and to the industry as a whole for the assurance of supply. So we're looking, so Toshiba's value to the marketplace is both in creating these new technologies, filling out a product line, but also stepping up and establishing the capacity through significant capital investments in a lot of places around the globe to ensure that the supply is there for the future. Exactly right. Toshiba is the most experienced flash vendor out there. And so we led the industry in terms of the floating gate technology and we are technology leaders. The industry is migrating into the 3D. And so with that, you know, we continue with a significant capital investment to maintain our presence in the industry as a leader. So when we think about leadership, we think about leadership both in consumer markets because volume is crucial to sustaining these investments, generating return. But I also want to spend just a second talking about the enterprise as well. What types of enterprise relationships do you guys envision and what types of applications do you think are going to be made possible by the continued exploitation of flash in some of these big applications that we're building? Doug, what do you think? Well, I think that new types of flash will be necessary for new emerging applications such as AI or instant recognition of images. So we are working on next generation flash technology. So historically, flash was designed for lowest cost per bit. So that's where how flash began to take over the market for storage from hard to strives. But there are a class of applications that do require very low latencies. In other words, they want faster performance. So we are working on a new flash technology that actually optimizes performance over cost. And that is actually a new change to the flash memory landscape. And as you alluded to earlier, there's a lot of differentiation in flash now to address specific market segments. So that's what we're working on actually. Now, generically, these new non-volatile memory technologies are called storage class memories. And they include things like optimized flash or potentially phase change memories or resistive memories. But all these memories, even though they're slower than say the volatile memories such as DRAM and SRAM, they are number one, they're non-volatile, which means they can learn and they can store data for the future. So we believe that this class of memory is going to become more important in the future to address things like learning systems and AI. Because you can't learn what you can't remember. Exactly. I heard somebody say that once. In fact, I've got to give credit. That came straight from Doug. So if we think about looking forward, the challenge that we face ultimately is have the capital structure necessary to build these things, the right relationship with the designers necessary to provide guidance and suggest about the new class of applications and then the ability to consistently deliver into this, especially for some of these new applications as we look forward. Do you guys anticipate that there will be, in the next few years, particular moments or particular application forms that are going to just kick a lot of, or further kick some of the new design, some of the new technologies into higher gears? Is there something, you know, autonomous vehicles or something that's just going to just catalyze a whole new way of thinking about the role that memory plays in computing and in devices? Well, I think that, you know, building off of the, you know, a lot of the applications that are utilizing NAND technology that we're going to see, you know, now we have the enterprise, we have the data center that's really starting to take off to adopt the value proposition of NAND. And then as Doug had mentioned, you know, when we get into the, you know, autonomous vehicle and we get into AI, we get into, you know, VR, a lot of applications to come will be utilizing the high density, low latency that the Flash offers for storage. Excellent. Gentlemen, thanks very much for being on theCUBE. Great conversation about Toshiba's role in semiconductor memory, flash memory and future leadership as well. Thank you. Thank you, Peter. Scott Nelson is the Senior Vice President and GM of the Memory Unit at Toshiba Memory America, Doug Wong, the member of the Technical Staff at Toshiba Memory America. I'm Peter Burris. Thanks once again for watching theCUBE.


My name is Dr. Roger Sluido. I'm the chairperson for the Zambia Community-Based Natural Resource Management Forum in Zambia. This forum is an umbrella organisation of communities who are involved in sustainable wildlife and natural resources management in Zambia. Community is actually critical and primarily producers of wildlife and natural resources, and therefore it is very, very important that communities have a say in all the decisions involving these wildlife resources. They are the people who live with them, they produce them, they bear the cost, so it's just as important that communities have a say on what happens around the resources that they live with. Speaking about myself, I grew up in the village, I've lived in these areas so I know what it takes, I know what issues, what challenges we go through, the human wildlife conflicts, people affected in many ways by living in these areas, so I have a personal experience, a personal story, and it's very, very necessary that people who live with these resources share their connection, their connection with nature, their connection with these wildlife resources because we also carry and bring out the indigenous knowledge. We have the indigenous knowledge that we know about what kind of species, we need to look after what kind of trees, what kind of plants, all those kind of things. So there's that indigenous connection between communities and their environment in which they live here. Hence it's very, very critical that they share their stories because that will help to also link it for instant scientific research, it also link it to policy making and so on, and it should be able to help government to make proper decisions. I think wildlife conservation or natural resource conservation, I think there are many ways in which that could be done, but I think also keeping the wildlife in the world environment, in their natural habitats, in their traditional way is very, very critical and very, very important. So we see a question where we need to let the wildlife live in the original environment. Of course there are management issues that may arise, especially species that are threatened or that are near distinction, that might have to be kept for instance in zoo or so on, but I think allowing the wildlife roam within this free-ranging area, roaming-ranging area is as important for conservation itself.


We have looked at both velocity and temperature boundary layers and we have obtained similarity solutions as well as integral solutions for a variety of conditions of the free stream velocity, the suction and blowing velocity and the pressure gradient which of course is accounted by free stream velocity variations as well as the wall temperature variations with and without effect of viscous dissipation. We now turn to another important class of flows called internal flows and that is the topic of my discussion today, laminar internal flows. I will explain first the relevance of internal flows with important definitions and prediction of developing flow as an example of application. Internal flows are principally of interest in heat exchangers where it is important to have knowledge of the pressure drop for a given length of the tube or what we call the friction factor and also the heat transfer coefficient or the Nusselt number on the tube side of the heat exchanger to facilitate their design. Modern heat exchangers of course employ ducts of both circular and non-circular cross sections. Sometimes even curved ducts are preferred or are necessitated in order to conserve space. Duck passages with internal insertions such as the twisted tape or coils are also popular. Optimally internally structured surfaces such as rib rubbiness, grooves and indentations are also used for augmentation of the heat transfer coefficient or the Nusselt number. Most of these modern applications represent examples of very complex terms as opposed to the very simple case of a flow in a round tube or flow between two infinite parallel plates. So solution of transport equations of mass momentum and energy provide means for obtaining FNNU which is of interest in design. In simple ducts, analytical solutions are possible. In more complex ducts however, one needs CFD solutions and unfortunately that would be a topic outside the scope of the present lectures. But we shall consider a few non-circular ducts and treat them analytically. In the slides to follow, I will show you a few examples of ducts of non-cross sections and structured internal ducts and also curved ducts.  The first one on the left here is of course the simple annulus with the inner tube and an outer tube. The flow is between the two tubes. Sometimes the space between the inner and outer tubes is also connected by fins and what we have is an annular sector duct. The fluid flows through this sector and all sectors behave in a similar fashion and therefore, interest is in an annular sector. The plate fin heat exchanger is of course well known to you. This is the top plate, this is the middle plate, this is the bottom plate and there will be several stacks of plates like this. The flow is cross flow in the sense then between the top two plates, the hot fluid meme flow from left to right and here in the bottom two plates the flow may be directed as shown here, the cold fluid. Again the two plates are connected by fins which form ducts of triangular cross section. Here the cold fluid flows through ducts of square or rectangular cross sections. They are very commonly encountered ducts in plate fin geometry of more complexity and in extremely small heat exchangers what are called mini heat exchangers or micro heat exchangers with very high surface area to volume ratios bordering on 1200 to 1500 meter square per cubic meter. Ducts of extremely complex shapes are employed. Here is an example of a duct which is moon shaped and what I have shown here is a half section of the moon x axis being the symmetry axis. This is the inner edge of the moon, this is the outer edge of the moon. Likewise, there are ducts which are of cordoid shape. Again x axis represents the symmetry axis and I mean the symmetry plane and this is the outer boundary of the cordoid duct. In nuclear rod clusters in a circular shell there are large number of rods kept. There is one rod in the center, then there are several rods in the first rod ring, then another set of rods in the second rod ring and so on and so forth. So, it may go like 1 6 and so this is a 19 rod cluster geometry. So, it would go like 1 6 7 and 12 in the outer ring making 19 rods. The flow of course, this is the symmetry plane. Again this is also a symmetry plane and the flow takes place in the interspace between the rods and you can see how complex the flow cross section then is. It is a very good example of a complex shaped duct that is encountered in nuclear reactors. The plate phoenix exchanger that I showed you here, the plates here are flat. In order to save space, many a times the plates are actually wound in a spiral and what you then have are several spirals starting from the center and becoming ever bigger in the radius r and what I have shown here is a typical section of a curved spiral plate heat exchanger deck. So, this is the outer wall, this is the inner wall and the duct itself has a radius of curvature r. The fluid is flowing through this and coming out like that. Another example is that of a plane tube with a circular cross section, but in which a metal strip of width equal to the diameter of the tube is twisted about the axis of the tube. What the tape does then is to divide the circular cross section into two semicircular ones and each semicircular cross section then twists along the axis of the tube as one goes down the tube in the flow direction. So, what you have are two semicircular cross section twisting about the axis of the tube and it forms a very complex curved duct with a non-circular geometry. Internally structured surfaces, the gas turbine blade is a classic example of how surfaces are internally structured. First of all, notice that this is the cross section of the blade and you will see ducts of non-circular cross section. Each duct has ribs in it sometimes straight sometimes at an angle as you can see here. Some ducts are straight whereas others are having a bend. In some part of the blade, you have a duct which has ribs and then one wall is perforated so that the flow goes this way and then also comes out with impinging air on the leading edge of the blade and the remainder air goes out of the blade through the top. Likewise, at the rear end of the trailing edge of the blade, you have flow coming in from here and which passes on through this perforation in this wall as well as some flow goes directly into this trailing edge passage. In this passage, you have number of pin fins, solid pin fins. They are designed to make the trailing edge strong and you have perhaps the most complex of internally structured passages or ducts that you can encounter in engineering practice in a gas turbine blade. A tube of this type which is extensively used in refrigeration and air conditioning industry has spiral grooves etched on both inside surface as well as the outside surface. These grooves are cut out. This is a copper tube and you can see how tiny the near surface structure is. In fact, the height of the grooves is quite small and if you have familiarity with turbulent laminar sublayer in a turbulent flow, then the height of the tube just exceeds the laminar sublayer. The purpose of the tube grooves is to make sure that the sluggish laminar sublayer is continuously disrupted and therefore, enabling enhanced heat transfer. Same is the purpose of internal rib roughnesses and so on and so forth. Our interest here now is on laminar flows. All the many practical applications are in turbulent regime. We shall take up the turbulent flow a little later but let us concentrate first on the laminar flow in a duct. Let us say the flow enters with a uniform velocity u bar let us say. As soon as it encounters the top and the bottom wall, there would be viscous action and therefore, the boundary layer development as shown here. Inside the boundary layer, there will be a reduction in velocity from its initial value and to compensate for that, there would be increase in velocity inside what is called the core region. For all practical purposes, one could imagine the core to be almost of uniform velocity but the velocity itself would be greater than what it was at the inlet. So, we have a region core region in which the velocity continuously accelerates and is greater than that of the inlet velocity but in the boundary layer region, you have a velocity which is lower than the inlet value. Ultimately, the boundary layers from the two walls meet. When they meet, we say the flow is no longer in state of development but has reached a state of fully developedness. By that, we mean that the velocity profile that is now generated would sustain itself without any change in the axial direction. Therefore, the fully developed flow is identified with the du dx equal to 0, where u is the velocity in the axial direction as well as the pressure gradient in the axial direction is constant. What is of interest from practical standpoint is the estimate of development length l v and l v as we can very well imagine would be a function of Reynolds number. The higher the Reynolds number, the higher will be the length l v. In this entrance region of the duct, analytical treatment is usually quite difficult except in very simple cases. For more complex cases of complex cross sectional ducts and so on and so forth or curved ducts, one really has to adopt CFD based procedures, computer procedures. Nonetheless, I would take up a very simple case as shown on the next slide. It is essentially a case in which these are two infinite parallel plates both in the z direction as well as in the x direction. The z direction being and the y direction is measured from the bottom plate going forward. The plate interpolate distance is going to be 2B. So, the distance between one wall and the axial symmetry is simply B as you will see on the next slide. So, we consider laminar flow between infinite parallel plates separated by distance 2B and in the entrance region using boundary layer approximations, the governing equations and the boundary conditions are as given here. First of all, you will have the continuity equation, then the momentum equation in which you have the convective terms and then the viscous term. The velocity at x equal to 0 for all y is the average velocity u bar with which the fluid enters the duct. The v in the inlet plane again is 0 and u bar at any cross section would be 1 over B 0 to B u dy would be the average velocity. At the symmetry plane, d u by d y at all x will be 0 and so will the v at the symmetry plane will be 0. At the bottom wall x 0, u will be 0 and so would be be 0. That means there is no suction or blowing into the duct. All this is quite familiar and understandable by now.  Equation 5 here shows that the pressure gradient is balanced by both the momentum change terms or the convection terms and also the viscous terms the d 2 u d y square. So, viscous friction as well as momentum change caused by change in velocity profiles along the length the duct balances the pressure gradient which itself varies with x. Now, what makes it difficult to obtain solutions to this type of equations is the fact that remember this first of all these are 2 equations and we have 3 unknowns u v and pressure. So, we really have a problem here that unlike in the boundary layers where we specify the pressure gradient we cannot do so in internal clause and we have to do some tricks. So, the coupling that is that exists between the continuity equation and momentum equation is due to convection terms here and that is what makes this equation set in non-linear equation set because of the coupling and we have to find ways to override this coupling. Now, this is precisely what was done by a man called Langar in a paper published in 1942 titled steady flow in the transitional length of a straight tube and was published in journal applied mechanics volume 9. He said the left hand side or the momentum change terms are functions of x and y, but we shall write them as beta square multiplied by velocity. Beta square is a constant at one cross section its value will change from cross section to cross section, but at a given cross section beta square is a constant and u star is a function of x and y of course, so that the left hand side and the right hand side I have the same dimensions.  In other words and we define f l the local friction factor as 1 over 2 d p d x into d h by rho u bar square sorry this should be I beg your pardon this should be d h over rho u bar square.   So, I introduce here u dash equal to u star minus r e by d x star. u by beta square d p star by d x then this equation if I substitute for u star and notice that this is a function of x only and therefore with y this will simply become d 2 u dash by d y star square minus beta square u dash equal to 0. Now, this is with boundary condition u star equal to 0 at the wall y star equal to 0 and at the axis of symmetry where y star is equal to 1 by 4 remember this is the this is the duct of length 2 b this is the axis symmetry we are measuring y this way. So, this is y equal to 0 and this is y equal to b, but d h is equal to 4 b. So, this becomes y star equal to 1 by 4 b divided by 4 4 b and this is also equal to y star. So, at y star equal to 1 by 4 the velocity gradient will be 0 the velocity gradient in y direction would be 0 and that is what I have the equation has 2 boundary condition this equation has 2 boundary condition u star equal to 0 at y star equal to 0 and d u dash by d y star equal to 0 at y star equal to 1 by 4. Now, this is a very familiar fin equation in heat conduction that all of you are familiar with and therefore, the solution is very simple it is a c 1 exponential beta y star plus c 2 exponential of minus beta y star and if I make use of these two conditions I can determine c 1 and c 2 they evaluate in the following way c 1 is Reynolds by beta square d p star by d x star divided by 1 plus exponential of beta by 2 and c 2 equal to c 1 exponential of beta by 2. So, this is quite straight forward algebra to really evaluate c 1 and c 2 which incidentally is a function of c 1 into exponential of beta by 2. Now, to evaluate pressure gradient we make use of the definition of mean velocity we said u bar is equal to 1 over b integral 0 to y u divided sorry 0 to b.  So, this is 4 times b and this would be u bar and therefore, b b gets cancelled. And you will get 1 by 4 will be equal to 0 to 1 by 4 u star d y star.  I know u dash as a function of y and therefore, integrate then you will see that you can get r e d p star by d x star equal to f l Reynolds equal to beta times 4 c 1 exponential of beta minus 2. So, knowing the value or assuming a value of beta you can always calculate beta c 1 and therefore, evaluate expression d r e d p star by d x star the local pressure gradient. Another quantity of interest is the central line velocity how does the velocity at the central line change of course, the velocity begins at x equal to 0 u c will be equal to u bar at x equal to 0, but it will go on increasing till the flow become fully developed. So, if we consider this equation again equation 10 this equation again then and write it at the axis of symmetry y star equal to 1 by 4 it will simply become d 2 u d y star square at 1 by 4 minus beta square u star c equal to r e d p star by d x star where it can be shown that the evaluation of d 2 u star d y star 1 by 4 is nothing but 2 c 1 beta square over exponential of beta by 4 and therefore, a little algebra of about 2 3 lines will give you u star c is a function of again beta and c 1. So, we have evaluated the pressure gradient local pressure gradient we have evaluated the local value of the central line velocity for a given beta which incidentally means for a given value of x along the duct. The next question is of course, which value of beta corresponds to which value of x because beta has been arbitrarily chosen numerical value and we still have to work out what is it the connection between beta and x. So, let us go back to equation number 5 this was the over original equation.      Therefore, that term goes to 0 and this term of course survives because there is a velocity gradient right at the wall.   So, I substitute for u star in terms of u dash and then carry out the integration and differentiation.   It is this that establishes the relationship between x star and beta that we find out because f 1 and f 2 are functions of beta. How is this done? It is done as shown here. We want to evaluate this integral. So, we first assign different numerical values to beta and generate functions f 1 beta and f 2 beta and tabulate them. Then we simply carry out integration by trapezoidal rule.  So, you have a value of f 1 60, f 2 60 and so on and so forth.  So, we have for each beta value function.   This is the trapezoidal rule which I just wrote. So, now of course, you can make beta arbitrarily large, very large. It can go up to infinity and on the other side will go to 0. I took several values and I found going up to 60 was quite good enough because as beta tends to infinity, x star tends to 0 and as beta tends to 0, x star tends to infinity. So, of course, in lieu of infinity one can choose any value. Now of course, once you have chosen beta values, you can also calculate for these beta values. You can calculate three more quantities. One is c 1, second one is u c and the third one is f l. So, these are the three quantities you can calculate. They are all functions of beta and once the integration relates the value of x star to beta, we know that these are the values that correspond to x star. Although large number of solutions were generated for very tiny steps of beta, I am showing you solutions for select values of beta. So, here are the values. At beta equals 60, c 1 turns out to be extremely small and negative. It corresponds to x equal to 4.60 into 10 to the power minus 6. Here, x is divided by d h, the hydraulic diameter and then divided by Reynolds number. u c star is simply the central line velocity divided by u bar and this is f l multiplied by Reynolds number which is the local friction factor. So, you can see for each value of beta, a value of x has been discovered. As beta goes on reducing, x goes on increasing and finally, for beta equal to 0.1, x is equal to 0.01, u c star becomes equal to 1.4, 998, almost 1.5. So, asymptotically, you can see from about 0.005 onwards, the change in friction factor or essentially the pressure gradient is very small. The change in central line velocity is also very small and essentially a state of fully developedness has been reached asymptotically at infinity. Of course, u c star becomes 1.5 and 24. This incidentally can be shown even from the analytical solution that we already have. So, you can see as the flow develops, the central line velocity increases, friction factor itself, multiple Reynolds number of course decreases with x. Solutions of this type can be generated, here I have generated them for flow between parallel plates, where the resulting equation is a simple fin equation. But you can also do this for flow in a circular tube, where the resulting equation is a Bessel's equation. Also in case of an annulus, entrance rigid of an annulus, the resulting equation is a Bessel's equation. The algebra there is much longer, but here it is a simple algebra and therefore, I chose to do the flow between parallel plates, which in itself is of great interest. This is the variation of friction factor versus Reynolds number, starts from the high value and goes down to a constant 24 at about 0.01. Likewise, the central line velocity goes from 1 and ends up with 1.5. So, fully developed friction factor is 24, fully developed central line velocity is u c by u bar 1.5. We can now treat this distance L v by d h r e approximately equal to 0.01. The behavior near the fully developedness is very asymptotic and therefore, one could not really fix precisely the value of development length, but purely by observation we can say L v by d h Reynolds of 0.01 is a good estimate of the flow development length, which we said was our objective. Now, all these results that I mentioned of the fully developed plow are well known from the u g tex, either from analytical solutions for annulus and circular tube or in the case of ducts of non-circular cross section where CFD analysis is used, you can get values of development lengths and I will show them on the next slide. But here note that instead of the local friction factor that I have plotted here, sometimes people prefer because the local friction factor gives you variation of the local pressure gradient, but people are interested sometimes to measure actually the local value of pressure itself and that means, what they define what is called as an apparent friction factor because this is what you will measure in an experiment. Apparent friction factor is defined as minus 1 over 2 p x minus p x 0 divided by x d h over rho u bar square and it is simply 1 over x 0 to x f l d x. So, our solution for f l can be integrated to get apparent friction factor and it would go something like just slightly above the local friction factor and again predict at long length you will predict that apparent friction factor is also into Reynolds number is again 24. So, let us look at the values of development lengths predicted for different ducts and here I have chosen a few ducts, a ducts of few cross section circular tube its development length is 0.05 l v divided by d h divided by Reynolds for an annulus of different radius ratios r i by r rho. So, if the inner radius is very small it is 0.01944, if it is 0.1, 0.17 and so on and so forth. Note that these values need not be monotonous because the value of d h itself goes on changing for different radius ratios and so does the value of Reynolds number which is a function of hydraulic diameter. So, these need not be monotonously increasing or decreasing the values are simply numbers to be used directly in an analysis. But notice that when r i by r rho tends to 1 this is r i and this is r rho, when r i by r rho tends to 1 which means r i is very very close to r rho then for all practical purposes the flow in annulus is much like the flow in between parallel plates and predictably you are seeing that the development length is 0.01 which we actually calculated through our analysis. Similarly, in rectangular ducts of side ratio b by a or essentially it is 2 v by 2 a then the ratio b by a gives you the aspect ratio. When b by a is 0 again when b is very very tiny you essentially get flow between parallel plates because a then is infinite and the l v by d h ratio is 0.01 as we predicted for 0.125 is 0.227, 0.254 to 7.5 and so forth. And when you tend to 1 that is a perfect square the development length is 0.0752 here is a result for semicircle this has been calculated by numerical analysis and l v by d h Reynolds number is 0.0622. So the development length normalized with hydraulic diameter and Reynolds number has a notionally fixed value for a given duct and is always as you will see when we go on to heat transfer calculations it is very essential that we know what these development lengths are so that we can account for their presence in the heat transfer analysis. So, the integral work of this type is almost now abandoned because most people use CFD based solution procedures, but it would be useful for you to know who were the early contributors to this very interesting aspect of internal flows and therefore I give you a few references. The first one is by Sparrow and Lynn published in 1964 it is called flow development lengths in hydrodynamic entrance region of tubes and ducts physics of fluids volume 17 another one by Hahn hydrodynamic entrance lengths for incompressible laminar flow in rectangular ducts published in 1960 Lundren's parent star pressure drop due to the entrance region in ducts of arbitrary cross section this is in journal of basic engineering 64 and then for annular passages there is the paper by Heaton Reynolds and Case in international journal of heated mass transfer. So as I said the flow in the entrance region is quite complex situation and one needs exact analytical solutions for classroom work can only be worked out for simple cases I gave you example of one case and then concluded with the magnitudes of the development lengths as encountered in different ducts. In the next lecture we will take up the case of fully developed flow inside ducts of circular and non-circular cross section.


What should engineering managers be thinking about during this COVID-19 pandemic? In these engineering manager 80-20 shorts videos, we're typically giving you tips for becoming better engineering managers. But in these times, everything is different. People are all working remotely or maybe you have been and will be for months. So something to think about during this time is to be human with your staff, right? To talk to them about themselves, their families, what's concerning them right now. When you start a staff meeting, maybe you don't jump in with, hey, how's your project's going? Or give me a project update. Let's jump in with, how's everyone feeling today? How are you doing? How do you feel with everything that's going on? These are questions that are different than the typical staff meeting questions, but they're what we need to be focused on right now to help everyone get through it. Because the reality of it is, is that there are a lot of engineering companies that I talk to that are still very busy. And so the inclination is, oh, everything's fine, our projects are on schedule, we're okay for now. But how are your people feeling? How are your team members feeling about all the uncertainty that's out there? And really about, you know, not being able to connect with other people as well by being isolated. So please, as an engineering manager during these times, focus more on your people than ever and ask them how they're feeling about everything and how you can support them to get through this. Please subscribe here for our weekly engineering manager 8020 shorts. And I hope that you and your family stay safe during these times.


Everybody forced here ripping 2023 certified football hobby 4 box number 17 Pick your team style. We've got Alan K with the Titans Andre has the Lions and drew with the pack Andrew P with the Packers Andrew T with the Bengals Cameron with the Chargers Craig C Cowboys Dana with the Broncos Daniel M. Cardinals drew our Colts George M Jaguars Greg Riem Buffalo Jason M. Giants Jeff S. Dolphins Jonathan L chiefs Joseph M. Washington Josh I Seattle Justin C Cleveland Keith B Vikings Mark W. Bucks Matthew S Texans Eagles Patrick E Steelers Peter a Panthers Robert R Bears Rory C Ravens Sean with the Rams Stephen V Niners Stephen W Jets Valerie with the Raiders William S patriots in Jauri with the Falcons and the Saints Jauri Okay, great taking a few spots in origins about first origins down to 11 ago Down to 11 ago now on the first origins Okay Gold team of Debo Samuel Tony Pollard Cowboys numbered 47 to 50 Cowboys healed it today certified stars Eagles Jalen Hertz Brian Bree C rookie Saints out of 275 certified stars of Stefan Diggs for the Bills rookie Jersey to 249 Cardinals Clayton Tune Got certified stars Stroud for Houston. Nice Stroud rookie Buck Stray Palmer to 399 Immortals Joe Thomas for the Browns rookie Jersey Broncos Marvin Mims the 249 that orange color match Fonte Adams calling cards with a uh Derek Stingley jr to 199 for Houston Mike Evans certified stars gold 4 of 25 for the Tampa Bay Bucks They Jalen Petrie certified potential auto to 149 for Houston franchise foundations Bengals Joe Burrow rookie Jersey Otto Aiden O'Connell Raiders to 199 His old lion is not helping him out very much today. He's taking a beating back there Nice one for the Raiders though for the rookie QB starter here for Valerie Marv Levy Immortals uh, yeah, we have a We have a torch. I'm whenever someone opens the shop door goes off Got calling cards George Kittle Niners It's a 99 Joe makes in Bengals Why does that one float upside down? That's weird Gold team CJ Gardner Johnson for the birds with a Jared Goff piece of the game Jersey to 99 for the Lions Calling cards mark Andrews for the Ravens Chris Olavade a 199 Saints He had a touchdown today, right? So Once James came in to start a hurl in the ball around. Yeah, that's right Certified star is Henry God rookie Jersey Jalen Hyatt Giants at 249 Yeah, I think it's like the ADT sound. I think it's like the the default ADT sound To 99 Joe Burrow franchise foundations for the Bengals Franchise foundations bears Justin Fields Anthony Richardson Colts rookie to 325 Nice card for Drew R in the Colts Cardinals won. Hey pats looking pretty good getting that first pick man Kellen Winslow Jonathan Allen out of 275 of the commanders Mike D. What up Mike D The place to be more Jackson calling cards saw scarter to 349 jets DK certified stars Seattle Freshman fabric rookie Jersey Otto is Tyler Scott bears the 349 You go bears Tyler Scott Lawrence certified stars Jags Christian Gonzalez pats rookie Otto out of 149 on the roll call You know watch the son of that football Mike ripping some uh, there were some breaks here Wasn't last buying Saints. Uh, I Here I can check real quick Congrats Do they win? Yeah, could they play? Um, forgive me. I truly don't know. I'm not trying to like troll. I I don't pay attention to football on sunday's guys Like sunday's a big workday for me Uh Saints No, they were they were not the last team purchase not in this one. Anyway Immortals Randy Moss got tank del rickett at 275 for the Texans nice tank Ah, that's right chargers Was the game good at least So I thought that was gonna be one of the better games of the weekend looking at looking at the slate How about that dude? Pretty comfortable stats too. Well, why is this It's all good scott. They may have been in like the next one All right guys, we got to get some spots filling here in the last three breaks of the night Let's get that football mixer going nine to go single digits We'll go off top three quarterback. Whoa, spencer See he Steve young there. Oh, is that a night moves? It's a night moves. That's a cleat SP of some sort here. I think I think it's night moves There's an arm. I see an arm Dalvin cook of vikings on the night moves sp Sweet one minnesota There we go Could be more sp is in the uh in this break and even the next one We had a case with I think two or three the other day, so Maybe we'll see some more Jalen hurts gold team the 199 for the birds Rikki to 325 parker washington jaguars All right top three receivers in the league right now CD lamb Hmm Tyree kill. What do you guys think? What do you guys think? CD lambs up there right currently right now CD lamb has to be up there Tyree kill Henry calling cards titans Patch card great patch six of 10 bills josh allen There we go bills nice card How are you kj and lamb? That's pretty fair That's pretty fair. I don't I don't know who There's some other there's some other pretty good ones right now though So luke keekley immortals jets to 199 erin rogers They've been the most consistent over the past month and a half Diggs is definitely close definitely close uh rogers to 199 for the jets rookie giants of 275 jalen hyatt Appreciate it. G took Kelsey gold team Pollard out of 349 cowboys Uh seguan certified stars giants rikki jersey kendre miller to 249 for the saints It's weird to not put jefferson up there, but he's been hurt so Yeah, like can't can't can't put him up there because he's heard Yeah, if he was healthy, uh, there'd be no without a doubt He's coming back. Hopefully next week certified stars aj brown eagles Tyreek aj keenan's up there too. That's that's true too shade. He's been doing super well And they've they've needed him too because they got nobody else right now. What oh shade palmer and mike willer out It's it's been tough rookie jersey auto duce vaughn at 299 for the cowboys We go cowboys. Yeah, I think digs is kind of close I don't I would put him in the top three currently, but he's definitely close calfry there certified stars colster 349 jonathan taylor DK franchise foundation seox. He's another guy that should probably be in the conversation at least He's uh looking pretty good recently He was clutched today too Dak patch 25 had a fantastic game today.  He's safely in the top 10 for sure. I think sun god So 99 is henry titans franchise foundations I probably take him over guys like digs right now And nice speaking of there you go. Justin jefferson jersey auto for the vikings said to 75 Spoke that into existence. I think I think I'm gonna I think I'm gonna take Full credit for that one. I'm gonna take all the credit for that I'm just getting by the way congrats vikings. That's sick. I'm sure who I'm sure who has a vikings does not care who takes credit or not Let's see who's got a nice j jettas Happy to pull that one very uh very good timing on that too Very good timing on that. That's going to Uh keith there you go keith And t higgins. Is that how you say? I still would i'm nasty. I got dak right now, dude. Dak's about to go on a tear nasty now Keep giving him bad defenses, dude. It's a 249 certified stars Lawrence jags eagles rookie to 149 nullan smith Yeah, adams, too It's still with adams though because the quarterback situation has been just Not even I show the quarterback situation that but also everything around him has been very bad Like you can clearly see their their o-line is atrocious as well So it's just a whole offensive thing Falcons rookie to 325 zack harrison See a lot of these guys. I didn't necessarily like That they're the reason that they're not putting up decent numbers, but he's had some monster games this year too There's saint brown jake hannah rookie jersey to 349 saints nihim hinds gold team bills rookie for the colts of 275 ebb and hull Bass misses here.  Did anybody even mention jamar chase?  We always forget one person man. We always forget one guy Evans for the bucks kendre miller rookie out of 99 for the saints There we go saints immortals dan hampton Texans auto Derek stingley to 149 another one for the Texans there Gold team young way coop for the falcons rookie jersey auto dorian thompson robinson browns out of 399 Is anybody thinking jamar chase and just like losing their minds. They just didn't say anything. We didn't bring them up Eddie no, they will always chargers. I'm convinced, dude They've literally always had a good quarterback. They literally went from rivers to herbert Without even missing a gap and they can't do anything. They always get hurt I'm not gonna say I'm not blaming anybody at the chargers, but They always get hurt. They're snakebitten. Something always happens, right? certified stars chase They will always chargers. I'm convinced Garrett wilson franchise foundations for the jets erin rogers to one or erin uh jones 199 for the packers Like they've had good rosters. They've had a lot of talent and then there's just injuries happen Whatever it may be, dude Because they're both really bad. That's how they have the same record Uh relics of laporta hainer Dak kendre miller josh allen Uh jalen hyatt's jared golf Marvin mimms clayton tune a dalman cook night moves sp Dude, i'm hoping the giants win some games here so the paths can Get up that draft board Autos of dorian thompson robinson derrick stingley justin jefferson A duce vaughn christian gonzalez tyler scott aiden o'connell and jalen petrie Thanks, everybody moving on to the last four boxes of the case


Hello. Today we're going to talk about adding a colored background to your PowerPoint presentation. So when you open up PowerPoint, you have a blank white slide. You are going to move your mouse up to the Design tab on the ribbon, and you can see all the different colors of choices that you have. Again, if you click on the down arrow, you have more choices. So as you run your mouse over, you get an idea of what the colored slide will look like. So that's a very easy way of adding color. Now there are also other ways here that you can add color, and that would be clicking over to the right side of your ribbon where it says Background Styles.  Here you see you have another list of choices. The solid fill will just give you a nice color background, and you come down to the color box, clicking on the down arrow, and you have other choices here. So if we make it maybe a light blue, and then you would click Close. Now if you want all your slides to be this color, you would click Apply to All. The other options you have would be if you want a little slightly different design called Gradient Fill. They have preset colors, so you can click on the down arrow, and this is very bright, or you can go a little softer, and click on the blue, and you can see the different tones. Okay, so let's keep with that one, and I'm going to click Close. Very good! Now it's time for your review. So what is this toolbar for? Yes, you click on the design to open up the theme toolbar to add more color. I want to add some color. What do I click on next? Yes, for more choices you click on the button that says Background Styles. Then you click on Format Background. What do I do with this pop-up box? You can click on Solid Fill or Gradient Fill. Then you click on the color down arrow to change the color. And don't forget, click Close, or you can click Apply to All.


Good morning. This begins the first of two lectures on psychiatric disease. I hope everybody, each of you, had a lovely Thanksgiving holiday. I certainly did. Today, we're going to talk about mood disorders, major depression, and bipolar disease. On Wednesday, we'll talk about schizophrenia. Ralph has already talked with you about autism. A few announcements. We're going to have discussion sections this Thursday as usual. Problem set six is due Tuesday as usual. We will post the final exam on Friday, December 4th, and it will be due on Friday, December 11th, 4.30pm at the usual place. No quiz this week. Instead, or in addition, you will get extra credit, one point, for emailing Ralph or Henry a question for Friday's session. So the question for Friday's session, at which we will both preside, is what is the challenge for neuroscience in the remainder of the 21st century? At least one reference from a journal, not a website or the text, but from a contemporary journal. And we have not received any request for a final review session, so we will take that, unless there's an outcry of dismay to mean that there will be no final review session. The TQFR, I'm quoting from last year's email, the TQFR survey period will open next Monday, maybe a week from Monday. Students will have several weeks to submit their reviews. I want to remind you that TQFR, that Ralph and I do indeed appreciate your feedback and as detailed as possible. And also it's very important to give feedback on the TAs, who as you know work hard and are practicing to be professors themselves, quality of the textbook, and you can of course compliment Jonathan Lew on his wonderful presentation of the reflex hammer, which was quite interesting. And then you can email the registrar.  Neither Ralph Adolph and I are psychiatrists, in fact we're not even physicians, so don't change any medical treatment that you might now be receiving on the basis of these lectures and don't give any medical advice based on these lectures or on the accompanying problem sets. This book here is abbreviated DSM-5. It is the Diagnostic and Statistical Manual of Mental Disorders. This is the fifth edition published by the American Psychiatric Association. The first two or three editions were rather thin. The fifth edition is rather thick. It still comes on one CD or one thumb drive though. It is basically the way a psychiatrist classifies and diagnosis a psychiatric disorder such as major depression or bipolar disease or schizophrenia or anxiety or autism or any of the other diseases that psychiatrists diagnose and that the National Institute of Mental Health supports research on. There is very little in DSM-5 about causality, very little about genetics, very little about any kind of prescribing or therapy. It's all descriptions, all fine grained subdivision of psychiatric disorders as has been classic for diseases for thousands of years. And in fact, there was a controversy beginning about four years ago when the then director of the National Institute of Mental Health, Thomas Insel, said, well actually DSM-5 is wonderful for psychiatrists but it's not very good for research. And he wanted, and he did in fact set up another kind of class, it wasn't a classification, it was a research framework in which one instead of diagnosing a psychiatric disease would instead talk about common characteristics of functional derangement across psychiatric diseases such as for instance aggression or mood. So that is called research domain classification. We don't have much time to talk about it in this course but it has become useful. And in the meanwhile, Tom Insel decided that after 13 years of leading the NIMH National Institute of Mental Health he was going to go and do some good for health research and for mental health research by leading a section of Google. So that's where Thomas Insel is now. But I think that the RDoC classification and the emphasis on understanding the pathophysiology of psychiatric diseases remains. Now there clearly are some brain areas that regulate mood. This is from the text, this is actually from Eric Nestler's review in Nature Reviews of Neuroscience several years ago. It remains true to this day. The frontal cortex is involved in mood regulation, the dental hippocampus, nucleus accumbens, amygdala, hypothalamus, ventral tegmental area, reward, the dorsal raffae which is mostly serotonergic, and the locus ceruleus which is mostly neuroadrenergic. So these are structures in the bottom of the brain in some ways they are also around the limbic system which is built around the ventricles. They have various transmitter systems, certainly glutamatergic, GABAergic. It is generally thought these days that monoaminergic transmitter systems, dopamineergic, serotonergic, neuroadrenergic play a greater role in mood disorder than the classical glutamate and GABA transmitters. But I'm not so sure that's true and neither are other modern neuroscientists and we will give you reasons for doubting this as we go on. So if we were reading DSM-5 or if we had graduated from medical school and we're doing now an internship in major depression, here is what we would find in psychiatry, here is what we would find for major depression. You can read from DSM-5, affective state of sadness, variety of human situations, loss of a loved one, failure to achieve goals, disappointment. Major depression which is different from depression is important and different because it differs in the intensity and duration or quality of the emotional state. DSM-5 then goes on to give some diagnostics, at least five of the symptoms that we'll discuss, each must be evident daily for at least two weeks. And most importantly as we will discuss for all psychiatric diseases that we'll discuss, you can't call a person depressed or mentally ill just because you don't like him or her or because it is as the Soviet Union used to do. It is politically convenient to get rid of a person by calling them a psychiatrically ill. The diagnosis of a psychiatric disease must include the requirement for clinically significant distress or impairment in social or job related or other important areas of life. So what are these criteria? First of all, a depressed or irritable mood. Now it's going to turn out over and over again that actually irritability plays a large role in depression. And most psychiatrists think that irritability plays a more major role in so-called depression in men than in women. Decreased interest in pleasurable activities or the ability to experience pleasure. This is also called anhedonia. Significant weight changes. Gain or loss depending on the person. This can be manifest in either way. Insomnia, sleep disorders. Some people can't sleep when they are depressed. Others sleep too much. Psychomotor agitation or retardation. This is not often seen in depression. People don't seem to be moving right. Fatigue, loss of energy. You can all think of friends who just didn't have much energy when they were depressed. Worthlessness or excessive guilt. Certainly a major aspect of major depression. Ability to think or concentrate. And the big one which we will discuss later on. Recurrent thoughts of death or suicide. So more characteristics. Untreated episodes. Major depression usually lasts about a year. Give or take a factor of two. Maybe 14 months. Most importantly, major depression is a recurring disorder which usually worsens with age if it's not treated. Again, the reported incidence of depression is three times higher in women than in men. I'm going to show you a bar graph of this later on. But in analogous situations men show more irritability than what you might call classical depression. Most importantly, and we have emphasized this in this course for years and in another course, major depression is treatable. There are treatments designed essentially for medical intervention medications which we will discuss today. There is in fact an experimental treatment called vagal nerve stimulation. There is deep brain stimulation in one of the regions we discussed in the first slide. And so just as you've learned about deep brain stimulation, which is very often employed in Parkinson's disease, deep brain stimulation for depression is much rarer but is done. And then one that is quite controversial but is very effective is electroconvulsive therapy. That is brief periods of high frequency stimulation which would cause convulsions if the patient were not protected seem to be temporarily therapeutic. And then over and over again people researchers find that in conjunction with somatic treatments psychotherapy is also very helpful. Cognitive behavioral therapy, interpersonal therapy, and then there are changes in attitude towards sleep in depression. Very nice New York Times editorial a couple of years ago claiming that some very detailed interventions in a person's attitude towards sleep helps. For instance, a person with depression should be discouraged from doing work in bed, should clearly delineate the experience of being in bed and asleep from the experience of being productive and awake. And then of course there are other treatments, diet, exercise, etc. So a major interest of my lab and of neuroscience in general is how psychiatric drugs work. The major revolution in the treatment of major depression occurred with Prozac or fluoxetine roughly 25 years ago. But very curiously the mood elevating effects don't take place right away. They require that the patient continue to use fluoxetine for several weeks. This is also true for any of the other depressants that are now on the market. Usually I don't give trademarks, but these include Xoloft and Paxil and Efexor and all of the other medications that your friends may be taking. So what's going on here? As I'm going to emphasize we know what fluoxetine in the other SSRI's selective serotonin reuptake inhibitors do on a time scale of seconds. In fact I've published several papers on this. They block serotonin reuptake mechanisms. But what is it that takes two weeks to work? Well the textbook by Heimann Nestler and Malenka, three excellent research psychiatrists, two of whom have been presidents of the Society for Neuroscience. They say well an adaptation to sustained increases in serotonin function that mediates the clinical effects of fluoxetine. Now you've heard me rave about the word adaptation or homeostasis or compensation. And you've heard me say that these words are in no sense mechanisms. They are best treated as adjectives. But where the adaptations occur and the nature of the adaptations still unknown. And yet the SSRI's and the SNRI's selective serotonin reuptake inhibitors or serotonin norepinephrine uptake inhibitors help roughly 50% of major depressive disorder patients. What do we know about SSRI's such as fluoxetine? We know that they bind tightly to and stabilize intermediate states of the serotonin transporter. I think I've showed you pictures like this. A transporter can be thought of as a channel with gates at both ends. The first gate opens, the substrates for the transporter enter the channel, the first gate closes, the second one opens up and all the gates, the second gate opens again. And the rules for binding and the rules for co-ions make it possible for a transporter to use the concentration gradient of sodium chloride potassium to reuptake neurotransporters once they have worked. And so there is a cycle of gates closing and opening, substrates binding, and fluoxetine binds tightly to and stabilizes intermediate states of the serotonin transporter so that the serotonin transporter cannot remove serotonin from the external solution, from the extracellular solution from the CSF, but in fact that serotonin remains. And as we've said, two of the three biogenic amine pathways do seem involved in antidepressant action. In part, this is because the antidepressants block their uptake. And in fact, the major argument for involvement of the biogenic amines still rests on the fact that the most clinically useful drugs, the so-called SSRIs and SNRIs, block serotonin uptake. So serotonin, 5-HT, we've discussed, norepinephrine, or noradrenaline, we've also discussed. Dopamine we're going to discuss in the next lecture on schizophrenia. So the question becomes, how does the interaction between an SSRI, a selective serotonin reuptake inhibitor, and the serotonin transporter-cert interaction relieve depression? And so most experts would say, well, how does blockade of serotonin reuptake relieve depression? And so there are possible downstream consequences of changed regulation of serotonergic systems. There's the short-term derangement of modulation of synaptic strength, possibly also of neuronal intrinsic properties. When maintained for quite a while, may cause the antidepressant effects. Long-term changes in modulation, as you know, from studying synaptic plasticity and from studying learning and memory. Long-term modulation of neuronal gene expression. And so the clinical observation that antidepressants usually take a few weeks to a month to have full efficacy suggests that modulation of gene expression plays the dominant role. But this is really unproven. The people who actually work with patients say that it takes somewhere between two and six weeks for an SSRI or another antidepressant to work. So therefore the experts say that the success of SSRIs implies participation of serotonergic systems in the brain, but in a nonspecific way. So here are the serotonin systems. There are the raffae nuclei in the midbrain. Here are all of the raffae nuclei in a sort of a washed out pink. And as usual with the monoaminergic system, the raffae nuclei project nearly all over the brain. You've seen these regions before. They all receive projections from the raffae nuclei. Now here's an interesting conundrum, which has not been solved. There are about 15 serotonin receptor genes. They have such wonderful names as 5-HD1, 5-HD2, all out through 5-HD8. But the one has six subtypes, 1A, 1B, etc. Most are GPCRs, but one 5-HD3 is a ligand gated channel. And there's only one serotonin transporter gene responsible for a reuptake of serotonin. And so you might think that if you want to manipulate mood, if you want to cause antidepressant action, then the way to do it is to find a serotonergic agonist that is selective for one subtype. A serotonin receptor, or two or three. And administer that serotonin agonist for weeks, and you would get the full benefits of antidepressant therapy with none of the side effects, which include digestive side effects, sexual side effects, etc. Despite roughly 30 years and billions of dollars and thousands of man hours spent at pharmaceutical companies and at universities, no such magic drug has been invented. Instead, the drugs that are useful are the ones that block the serotonin transporter gene, which exists all over the place. So that does not seem very selective, and it is another way of putting forth the conundrum about how antidepressants work. Because they are active, because they are effective for only 50% of patients, and because they have unwelcome side effects, it would be very helpful to be able to improve them, but nobody knows how, because nobody knows how they work. There are, in the Rathae nuclei, there are two serotonergic fiber types in the brain. Here is immunocytochemical labeling for serotonin. The small arrows are the so-called D-system. The large arrows are the so-called M-system. And these have really been confirmed, it may very well be, that the D-system activates ligand-gated channels because there are very small regions and can give precise liberation of serotonin, whereas the M-system has a more diffuse effect that activates the GPCRs. So nobody is sure what the difference is in the serotonergic systems. I think that I will skip this and go on to a possible role for a growth factor in depression. We have discussed neurotrophic factors, growth factors in this course. A particularly well-studied one is brain-derived neurotrophic factor, BDNF. And it seems to be true that SSRIs enhance, increase the expression of BDNF, mRNA, and protein. And it is also rather clear, so the treated state here would have lots of BDNF release and lots of new synapses. And those synapses would occur because the SSRI has released BDNF, brain-derived neurotrophic factor. And it is very clear that BDNF causes the enhancement of synapses. It also has several other undesirable properties, such as causing seizures. But it has been shown over and over again that SSRIs do release BDNF. How they do this is not at all clear. And that BDNF itself may be involved in the mode of action of SSRIs. Why this takes two weeks is not clear either. Or two to six weeks. So another theory about antidepressants is that they cause adult neurogenesis. Ralph has told you about adult neurogenesis. And it is fairly clear, at least in rodent models, that antidepressants, light growth factors, do increase the number of new neurons born, especially in the hippocampus. And these new neurons that are born are inhibited by some phenomena and go into the hippocampal circuitry and are influenced by inputs from other brain regions. And in turn go to influence other outputs such as the amygdala and the nucleus accompaniment. And so one answer to the puzzle of how SSRIs work may be that they cause the proliferation of neurons in restricted regions of the brain. And as Ralph has explained to you, it's now clear that even primates do have adult neurogenesis. So this would explain nicely because it takes a while for new neurons to be born, to migrate, to reach their target. This would explain rather nicely how it is that SSRIs take so long to work. In the subgranular zone of the hippocampus in the dentate gyrus, the new neurons basically are born into this particular zone. There's also a zone that gets into the olfactory system and they do differentiate and they become incorporated into neuronal circuits. So they proliferate, they differentiate, and they get into new neuronal circuits. Now the problem is of course that even in a rodent where this has been very well studied, the number of new neurons born and encouraged by SSRIs and by antidepressants is rather small. And furthermore, not all antidepressants cause neurogenesis. And the way to show that neurogenesis is necessary for SSRI action, for antidepressant action, is rather crude. You irradiate the brain, stop new neurons from being born, but you damage a whole lot of other processes with this as well. So some antidepressants are not SSRIs but SNRIs, serotonin and neurodrenaline reuptake inhibitors. And so again, most experts ask, well, how does blockade of neurodrenaline uptake relieve depression? And here are the neuroadrenergic cells in the locus ceruleus of a rodent brain. They too, like the serotonergic cells, project almost every region of the brain. There's some discussion about the hippocampus, whether actually the neuroadrenergic neurons project to the hippocampus or not. So one very exciting new set of results is the phenomenon of ketamine. Now we've discussed ketamine as a channel blocker, as a blocker of NMDA receptors, but it is found that ketamine at subanesthetic concentrations is also an antidepressant and that it exerts these antidepressant effects much more quickly than other antidepressants. It takes only a couple of hours and these effects take a couple of days, if not a week. This clinical observation has actually been known to veterinarians for decades because ketamine is used for animal surgery. The observation that you could use ketamine in low subanesthetic concentrations as an antidepressant has been in the literature for 15 years and at least one drug company is trying to make ketamine into an FDA approved drugs. What do we know about the effects of ketamine? One is that they involve BDNF synthesis and release, not surprising, in view of what we've said about BDNF. Another is that they probably occur not in the cell body, not in the nucleus, not by transcribing genes, but they do involve protein synthesis in the dendrites. And so there is the classical outside in view of how ketamine acts and there are good papers in science and nature about the fact that ketamine, a well-known blocker of NMDA channels, prevents those NMDA receptors from acting when it gets decreased calcium flux. Remember that NMDA receptors are quite calcium permeable. This decreased calcium flux acts on calcium-activated kinases. These calcium-activated kinases then change some of the proteins involved in protein synthesis, not gene activation, but protein synthesis. So new BDNF is synthesized in the endoplasmic reticulum in the dendrites, goes out through the Golgi apparatus and causes the release of BDNF. And that most people agree would be enough to change behavior maybe cause antidepressant. So that is the classical outside in theory. I published a couple of papers suggesting an inside-out idea for ketamine action. In the inside-out idea, which is very much like the ideas about nicotine, ketamine can gain and lose a proton at this immune group when it has lost the proton that becomes neutral and is quite permeable to membranes. And the question, and therefore enters the cell, and this has recently been shown by other groups. And the question is, how does this lead to BDNF secretion in two hours or so? That's an interesting problem, which one of your students, Alice Sue, is going to tackle as her rotation project. And when she's finished with that, she will conquer other problems in psychiatry. Right, Alice? Okay, so now we're going to switch to from major depression to bipolar disease. There's a clear distinction in DSM-5 and other places. We're going to follow our usual method of talking about a clinical description of a neuroscience disease, about its genetics, possible causes, about heterozygous advantage, and in fact here there is one, and about therapeutic approaches. Again, we go back to DSM-5, and bipolar disorder appears to affect between one and one and a half percent of the population in all modern societies. It's a mood disorder, which formerly turned manic depressive disorder because patients have one or more high functioning or nearly manic episodes alternating with major depressive episodes. Typically, it occurs a bit later than major depression in a person's mid-20s and unfortunately bipolar disorder often leads to suicide. So a manic episode is, again, you have to talk about the distinction between calling a person manic because he's very productive or happy and a market impairment in a person's function either in his job or in his studies or in his social life. Abnormally persistently elevated, expansive, irritable mood, including irritability, possibly patients with this disorder get hospitalized, and then there are additional symptoms, inflated self-esteem, a person has grandiose ideas. Very often patients who are manic have decreased need for sleep. You often see that patients who are manic really talk a great deal more fast than usual. There is pressure of speech. There is a flight of ideas going from one topic to the next. A person can be distractable and a very marked increased involvement in golden activities. And a person who is in a manic episode can indeed participate in pleasurable activities, sex, extreme sports, with likelihood of painful consequences. So this then would be a person with a manic episode. So DSM-5 now has the same subdivision of mood disorders as DSM-4. There are the unipolar disorders, which we discussed at the beginning of the talk today, major depression and a less severe form dysthymic disorder, and the bipolar disorders. And there are three types of bipolar disorders, and the psychiatrists have cleverly enough called them type 1 and type 2. Bipolar 1 is really the classical full-florid episode of enormous manic episodes and enormous depressive episodes. Bipolar 2 is less manic, but just as depressive, and bipolar 3 is less obvious in both directions. Now, when DSM-5 was being written, there was quite a controversy about whether patients could actually be distinguished between bipolar disorder and unipolar disorder. It was thought, for instance, that a large number of patients with major depression might be reclassified as maybe type 2 or cyclothymic bipolar disorder. In the end, that did not occur. It cares how you classify patients. Well, the reason that it's important to classify patients as either bipolar or unipolar is that most of what I have told you about medicating unipolar depression, that is, using antidepressants, using SSRIs, is pretty strongly not advised for bipolar disorder. With a bipolar patient typically giving an antidepressant precipitates a manic episode. And that is very bad. And so probably, again, Ralph and I are not psychiatrists, we don't prescribe, but a major mistake in the modern medical community is to give a patient showing signs of depression and SSRI when that patient is actually bipolar, you get a full-blown manic episode which could cause a crash and very severe consequences. So what are the genetics of bipolar disorder? I have not told you at all about the genetics of depression because they are quite complex. I will give you a whole discourse on the genetics of psychiatric disease on Wednesday when we talk about schizophrenia because that has been a successful exercise within the past year. We all thought actually that the success of genome-wide association studies for psychiatric disorders would first bear fruit for bipolar disorder and possibly then for schizophrenia. In fact, that has not occurred. Schizophrenia has been nicely mapped, although still confusing, bipolar disorder has not been mapped genetically. It is very clear that there is a strong genetic input. Concordance among twins is one way to look at a genetic input. It is not clear because in some cases concordance among twins could have to do with environment. But according to a narrow definition, that is if one member of a twin pair has bipolar disorder, does the other one also. According to one narrow definition, monozygotic twins, that is identical twins, show a 79% concordance. That is if you find a member of a twin pair who is bipolar, there is a 79% chance that his twin also has bipolar disorder. And if they are reared apart to separate the effects of nurture from nature, there is not much of a difference. The concordance drops remarkably for dizygotic twins, that is for fraternal twins rather than for identical twins. So this is a very strong indication that genetics plays a role, although it doesn't tell you how many genes are involved in what those genes do. Any questions about concordance? Again, we will talk about genetics of psychiatric disease a great deal in the next lecture. Passable causes of bipolar disease? Well, and remember here that if we took the general population and asked for concordance among members of the general population, if you find a person with bipolar disease and then wait for the next person to come by the red door or Starbucks or wherever, the chances are only one to one and a half percent that that next person will be bipolar. But if that person is a member of an identical twin and the twin walks up at 79%. Okay, so we are going to talk about schizophrenia on Wednesday and we will say that for each advance in neuroscience, somebody has, or in biology in general, somebody has tried it out on bipolar disorder as for schizophrenia and there's actually no satisfactory explanation. There are hypotheses in terms of properties of circuits and early developmental events and hypotheses no longer emphasize individual neurotransmitter systems. So, I've been promising to tell you about a heterozygid advantage for bipolar disorder and perhaps the best place to start is the writing of Kay Redfield Jamison who grew up in Pacific Palisades, went to undergraduate and graduate school at UCLA and is now a professor of psychiatry at Johns Hopkins. And so her book isn't, one of her books is entitled Touched with Fire, Manic Depressive Illness and the Artistic Temperament and basically she finds that an inordinate number of highly creative people seem to have bipolar disorder. In fact, her own biography, She is Bipolar, is entitled An Unquiet Mind. She talks about growing up as, well, not growing up as, but about her first manic episodes and about her medications and about the wonderful life she now lives, but completely medicated. And so the thinking that she has espoused and that others have espoused is that a small dose of genes leading toward bipolar activity, goal-directed behavior, fascinating behavior, interesting talks, dynamic, causes a person to get ahead in the world. It's a strong advantage if one doesn't have too many genes, but too many genes does cause bipolar behavior. So here are the writers that she lists in her book, Kay Redfield Jamison, Composers, Poets and Artists. Of course, and this means you're not responsible for this list, obviously. Of course, in a modern lecture, the person who might most typify bipolar behavior would be an artist, because we could show his pictures. And Thanh Gokha often comes to mind. He was quite productive in his rather short life. He had 750 paintings, 1600 drawings, 700 letters. Like most European artists in the 19th century, he went to Paris in order to be his most creative, and it was in his late 20s, naturally, and when he was 35, he was hospitalized first.  He then went to the French countryside, and a couple of years later, he shot himself. So here are the self-portraits. They get more and more stylized as he comes into his own very definite impressionist, but uniquely impressionist style. Here are two pictures that he painted of his physician. At the time there were no psychiatrists. Dr. Gache would have called himself maybe a neurologist at the time. So this was an earlier one in which he get a very nice portrait of Dr. Gache. I am told, incidentally, by one of my MOOC students who identified this, that it is digitalis. So he was thinking about medications that came from plants. This is a later portrait of Dr. Gache, clearly very stylized, very emphasized one might possibly say manic. And statements like this let us know that Fengach was grandiose, to say the least. And so his paintings got more and more abstract, more and more stylized. This was one of his latest paintings. Probably his last painting, Crows in the Cornfield, one of his most famous, occurred just a couple of days before he shot himself. So it's clear that people with bipolar disorder are often fascinating in the early stages. And we provided examples from the arts. In fact, a psychiatrist once told me that everybody needs to fall in love once with a bipolar person until they learn their lesson. Also people with bipolar disorder, although we've talked about the arts, seem to be overrepresented in many high-functioning environments, including students and faculty at prestigious college campuses. So this brings us up to the topic of suicide. And Caltech counseling is very good at mental health and counseling. In the U.S. these days, there are approximately 30,000 suicides per year, more than the number of homicides. It is the third leading cause of death in adolescence. Males outnumber females by something like four to one. And this may simply be because males succeed at suicide more often than females do.  Of course, if a person has not presented himself to a psychiatrist before he kills himself, you don't know. But most people have in fact presented to a psychiatrist before killing themselves. So here we have a graph that I promised you. It's called the daily, the disease associated life years. This is a statistic compiled by the World Health Organization. Sorry, disability adjusted life years. And essentially this represents the amount of productivity, the amount of production lost to disease by people in the prime of life. And so neurodegenerative disease, which mostly strikes older people, is not represented here. It's really lost working years. And the units are incomprehensible. I've never figured them out. I've tried to ask people who work for the World Health Organization. They can't help me either. But the diseases, the psychiatric diseases that we are discussing this week, unipolar depressive, bipolar depression and schizophrenia are very high on this list of disease causing lost productivity. And this is a danced society, people in the prime of their life. But you actually see the same kinds of statistics, the same kinds of results in almost every society in the world. So unipolar depressive disorder, very high, very large numbers of people. And highly apologetic, very hard to map genetically. Bipolar also very important. Schizophrenia we will discuss in the next lecture. Alcoholism, we don't have time to discuss here. And there are a couple of other neural diseases as well. Hearing loss, which causes major losses in productivity. So what about therapeutic approaches to bipolar disorder? Why is it important to have therapy for bipolar disorder? It's because many bipolar patients avoid therapy or they're partially compliant. They take their medication and primarily because they don't want to give up the pleasant feelings during the manic phase. And the problem here is of course that patients who do not comply with their medication risk suicide. So what are the therapeutic approaches? Well, there's surgical and electrical intervention, surgery to remove large portions of the brain that was done in the 50s and 60s. It was called psychosurgery. It is no longer done. I've mentioned the electroconvulsive shock therapy. I mentioned that it's not convulsive in the usual sense anymore because it's administered under anesthesia. There are various ways to put the electrodes to make the pulse widths to give to various frequencies of stimulation. There's no doubt that electroconvulsive therapy is a highly effective treatment for either major depressive disorder or bipolar disorder. We don't know how it works. There have been 100 therapies to account for the efficacy of electroconvulsive therapy. And again, you won't be responsible for this, but here is a reference to a society whose meetings I attend on theories about electroconvulsive therapy. The most basic statement that people make is, well, you're rebooting the brain. What does that make? What about, and again, I emphasize that it's usually a bad idea to treat bipolar disorder with antidepressants because this causes a manic episode. Then there are drugs for bipolar disorder. The simplest drug for bipolar disorder is lithium ion. And here we are, lithium in the periodic table, very simple, monovalent ion. The therapeutic effects of lithium also included delay, which is not explained. They occur in about five days. They require several weeks. And patients who are on lithium need to be monitored continuously because at higher doses, the typical lithium dose that's effective in the blood is a couple of millimolar. But at higher doses, lithium interferes with many ion channels, many transporters, and can typically cause seizures. So patients need to be monitored very carefully. And then there are additional treatments for bipolar disease, valproic acid, also a very simple molecule. In this case, it's an anti-convulsant. They require several weeks. So here from the early days of lithium in the 50s are notes from the first person who tried lithium on patients. He was an Australian. These patients had manic phases or manic depressive phases. He began lithium therapy, maintained it in the manic and depressive phases, were dramatically reduced. So how does lithium act? Well, we really don't know. But most ideas about lithium assume an intracellular target. And as I mentioned, lithium goes freely through some channels, freely through some ion couple transporters, typically substituting for sodium. And so most of the ideas about lithium involve inhibiting enzymes, and most of those enzymes manipulate high-energy phosphate bonds. They are ATPases or kinases. And lithium would compete for sodium binding sites at those enzymes. But this is really a very confusing field. And despite the simplicity of the lithium ion, we actually don't know how lithium works. So we have gone for the entire hour. I will be at my office hours today from 1.15 to 2. Ralph left any comments from TAs? No comments from TAs. See you Wednesday.


Now, we know you from Africa. Uh-huh. But, nigga, you're from the Bronx. Yeah, from Naysay. From South Bronx. Naysay, the Bronx is the dirtiest part of New York. Is that the truth? Dirtiest part, probably, of Brooklyn. Oh, I ain't never heard of that. I ain't never heard of that. I ain't never heard of that one. Yo, we don't do York babies as bad as that.  I know it's a Brooklyn nigga that said the Bronx is the dirtiest part. And so I got to give it right back to them. It was definitely a Brooklyn. That's it.