Good day, it's Professor Resnick again and today I want to first summarize this business cycle that Marx presents to us in Volume 1, Capitalist Business Cycle. So let me begin in terms of what we have already done here before. The capitalist has a capitalists have a rate of profit, let me put this on the white board. They have a rate of profit R for each and every capitalist and that of course again is the surplus value divided by the C plus V and they take the surplus value that is the board of directors of these these respective capitalist corporations and they distribute it to expand divided by C plus V plus all the other distributions that the capitalist enterprises engage in and I call this if you recall K star plus lambda and let's assume that that capitalism is all the capitalist enterprises are going through an expansion so that this is going up and hence this is going up this is going up so we have the we have a capitalist taking their surplus they're growing surplus the rate of profit is growing and they're accumulating more and also expanding their demand for credit the demand for managers the demand for for rents land land and so forth it's a general capitalist expansion this is going to impact as we saw markets so the so this expansion in value is going to impact all the markets that is the demand for labor power the demand for means of production are all going to rise and also the demand for credit the demand for managers the demand for land and so forth all these are going to rise so these demands over here are associated with the lambda these demands associated with both the K star and the lambda demand for productive and unproductive labor power the demand for productive and unproductive capital is as a generalized increase in demand in the society okay that's what expansion means that the markets are being affected by the demand curves shifting to the right across all these markets okay and this in turn if there's no other assumptions made all of this over here is going to say there's going to be a general rise in prices prices in all these different markets that is the price of labor power will rise the price of means of production will rise the price of credit that is the interest rate will rise the salaries of white collar workers that is managers will rise and of course rents will rise in the economy okay so it's going to be a general inflation a rise in market prices of all these inputs into capitalism that may cause that may this all of this may cause then a contraction and the argument here is that the cost rise so that the I'll put new here the new demands on the surplus may exceed the surplus and hence the capitalist have to cut back assuming they don't raise the rate of exploitation which they could but assuming that that doesn't happen then this is a kind of crisis caused the capitalist by the very expansion of capitalism and so the expansion where we started carries within it the seeds of contraction that's a Marxian argument about the business cycle itself can arise out of the very development of capitalism the expansion can cause a contraction okay and businesses capitalist businesses start to cut back because cost of you know the question is how much they cut back no one knows the answer to that question a b the very contraction itself helps to solve this problem because when the contraction occurs the demand curves for credit the demand curves for means of production the demand curves for labor power the demand curves for land for managers and so forth begin to shift back which helps to correct the same problem of an excess demand of these respective markets as the demand shifts back so as the demand shifts back you have excess supplies of labor power reserve army the unemployed excess supplies of means of production credit managers and so forth and hence the ironic twist is that the the the crisis itself helps to solve that crisis okay the initial crisis which was the demands shifting to the right prices rising but then the price rise creates a crisis for each and every capitalist they start to cut back some of these expenditures that shifts the demands to the left and we have a solution to the initial problem okay that doesn't have to happen that that that crisis okay that's only one part of the story the other part of the story that which I presented to you and it's in your reading readings the other part of the story is that this price increase may also lead to let me list it here let me you know there's so many of them so what I'm arguing here there's no inevitability for the contraction the expansion could continue so part of it is that the the capitalists themselves could expand and continue to expand because they get on the revenue side higher prices as I showed you it is true on the cost side they have a problem but on the revenue side they're selling their goods for higher prices for wage goods and higher prices for means of production and hence they'll expand because the this implies that their market rate of profits have risen so that'll induce them to expand that'll shift their supply curve to the right and therefore the prices will not go up as much as you as much as one would expect by the same logic the prices of means of production will rise the prices of means of production will rise so those firms that are producing means of production will expand because their profit rate has expanded because prices have gone up and hence prices will not rise as much as they would otherwise they may not rise at all they could even fall because of this rise in the profit rate here so you gotta you know you got on the cost side prices are going up but on the revenue side the prices of things that they're selling wage goods and means of production are rising and hence that and helps the expansion continue B credit may expand that is you won't get this rise in interest rate you would expect why because the supply of credit shifts to the right why because the state itself intervenes into the system to pump up the money supply which makes credit cheaper so the Federal Reserve Board in the United States intervenes into the market to supply more credit preventing the interest rate from going up okay see the supply of let me write it down here the supply of labor power shifts to the right in the labor market why well in the United States the experience over the last few decades is one of immigration legal and illegal women leaving households and and and entering the labor force to sell their labor power and then returning to the household to take to still do their jobs within the household so the you know as the feminists have shown quite strikingly women have two jobs one in the household one of the household but focusing on on the household how on the outside the household that means that women increasingly sell their labor power outside the household coupled with immigration legal and illegal that shifts the supply of labor power to the right and hence the the the price of labor power doesn't have to rise as much as it did otherwise you can even stay the it could it could fall okay below the the value of labor power giving a benefit to the capitalist the supply of means of production can also shift to the right and hence you don't get the increase here so on the supply on the supply side of the means of production you have two forces going on okay number one the supply of means of production you can shift to the right because the profit rate of the means of production industries goes up and hence the existing firms will have a tendency to increase their supply because it's profitable to do so but then there's new entry okay it's two two effects are occurring here one the existing firms can increase their supply and number two new firms can enter the into industry attracted by the higher profit rate so in the United States for example the firms that are producing means of production can expand induced by the higher prices they'll shift their supply to the right but also new firms can enter the industry foreign foreign means of production produces can export to more to the United States because the favorable prices and those will be increased imports into the United States which will enable the supply to shift to the right and give me another one you know this many of them let me give you two more okay the demand for labor power going back to the labor power market the demand for labor power may not shift to the right as much as one might expect it'll shift to the right but it may not shift to the right as much as one would expect and hence the price of labor power may not rise as much and that's got to do with a rising or composition of capital that is businesses may yes expand and purchase more labor power means of production but they may be portion purchasing proportionally more machines than they are labor power what the economists like to say the capital labor ratio is rising and that means that the demand for labor power will not shift to the right as much as it would otherwise because the capitalists are deploying more machines than they are labor power and hence there'll be less of a tendency for the price to go up that's kind of the computer revolution which is good in the states and elsewhere okay so it's the replacement really of labor power by by machines the other one works on the supply side of labor power suppose like in the United States unions are very powerful so they're able to charge a price unions use their power to get a price of labor power higher than its value well if the state goes on the attack as it has an orbital you know since president Reagan gone on the attack against unions it reduces their ability to get a price a market price higher than the unit value of labor power and that in and of itself will reduce if not a road the ability of workers to get a higher price of labor power when the market labor power market changes so there the market forces are now operating more than they ever did before so if you combine an erosion of union power a higher or organic composition of capital and a shift in the supply of labor power to the right because immigration you have a situation in the United States in which the price of labor power need not arise in fact it could even fall in the US with an expansion so that gives you an idea how there's no inevitability for the contraction to occur because all of these imply you know an expansion can continue so you have these counters you know counter forces operating you know and one is uncertain exactly if the forces on the contraction side the rising prices will be contract market prices will be contracted on the on the other side the revenue side to offset them and produce this continued expansion let me stop there on this particular summary of the extract of the contraction expansion sides of capitalism


Hi, my name is Angela Kegler and I'm going to be the instructor for the following course. You may be wondering to yourself, what does she know about this course? Well, allow me to share with you that I do have a PhD in organizational development and I have several years experience leading organizations. So that gives me the unique opportunity to share with you that I have both the academic experience having sat in your shoes in classes watching instruction on the content that you're about to learn. On the other hand, I've also led organizations which gives me the practice or the practical experience of seeing this firsthand in organizations. With that scholar practitioner experience, I'd like to deliver the content to you so that you can take this and turn it into something that you can use in your workplace. I hope you enjoy the class and you learn a tremendous amount. Happy learning. Let's begin with the critical thinking process. In this lesson, we'll look at critical thinking procedures, how to establish the problem, determining possible solutions, introducing your solutions, individually critically thinking, critical thinking as a collective effort, business trends in critical thinking, process improvements, internal empowerment, continuous overall improvement, and obtaining the right state of mind. Let's first begin with the critical thinking procedures. When we are critically thinking, we want to establish what the problem is. This is the first step in the process in which or the procedure in which we think critically. We have to understand what exactly is the problem. This isn't always easy. There may be multiple problems or it may be that there are multiple people involved in the process that have to help to identify what exactly the problem is. They may believe that the problem are different things. So establishing what the problem is is the first step to critical thinking procedures. Once you have identified and established the sure problem and have everybody on the same page, you can move forward with exploring what determined possible solutions exist. Determining possible solutions can be an exciting process because it allows you to open up your mind and explore various solutions that may or may not have been tried in the past or may or may not work. Being innovative, thinking through a variety of different solutions, even some that may not be great solutions, can open up possibilities for the organization to improve in ways that have never been done before. After determining some possible solutions, then you have to pare down the process into implementing the solution that is correct and right and best for the organization, the situation, and the individuals involved. Let's dig in to establishing the problem. As we've indicated, it's the first phase in which the problem is separated from the symptoms and it is defined. When you establish the problem, again, separating the problem from what the symptoms are is think about separating the problem from the people. Any time there is a problem, chances are there are people involved. And sometimes the people involved can cloud our perspective on what the real problem is. So if you can establish the problem by separating it away from the individuals who are involved in the problem, then you can focus on the problem and identify all the parts and processes and issues surrounding the problem. Creating a problem statement will help you to understand the problem so that you can move forward in developing a solution. In addition to creating that problem statement, you want to communicate that problem statement to the individuals who are involved and who are also facing this problem. This ensures that you can put all of the people who are involved on the same page and that everybody's focused on what the actual problem is as opposed to the symptoms or other individuals involved in the problem. The second phase is determining possible solutions. And this process, as I said, can be exciting. It involves six separate steps to determining what these possible solutions may be. The first one is to analyze the problem. As we said, we have to define and ensure that we know what that problem is. By analyzing it, it is breaking it down into understanding maybe the causal effect, looking at all of the parts and pieces of the problem. The problem may involve multiple sub-problems and ensuring that you analyze it and understand the problem to a depth and breadth that you can now address it. The second step is to gather information. When you gather information, imagine as if you are putting together a large puzzle. And you have to ensure that that 500-piece puzzle, which is indicated on the box, has 500 pieces in it. You want to gather all of your pieces, gather all of the information. And this can take time. If you do not gather information and spend time at this step, the problem or the solutions that you seek to put in place may not be effective. So taking time to gather your information, getting all of the pieces is very important. In the event that there's information that you cannot find, don't try to make something up. Think of that puzzle. If you only had 499 pieces, you can still see the picture. You don't have to abandon it just because one piece is missing. So gather what you can, and don't fill in the gaps just yet. The third step is to go ahead and interpret your information. From the facts that you have gathered, the pieces of the puzzle, start to present it in a way that it starts to form a picture. Interpreting the pieces and the information that you have gathered in such a fashion that you can understand exactly what the parts and problems are. As I said, the problem may have subproblems. So as you start to interpret your information, confirming understanding with individuals who are engaged in the problem and interpreting what their perspective may be, looking at this problem from a variety of different angles and different perspectives will help you in looking at possible solutions. The fourth step is to configure solutions. A best practice in configuring solutions is to look at getting various individuals involved so that you can get a breadth and depth of solutions and making an entire list of them. Exploring those solutions to understand which of the solutions will best suit the problem, will best suit the individuals involved, is ethical as well as practical, and can solve the problem. As you configure these solutions, it is incredibly important to get input from those individuals who are engaged in the process. Once you engage them, you can move on to that fifth step, which is agreeing on solutions. Agreement can sometimes be difficult. We'll talk a little bit more about how groups can come together to agree on solutions, but agreement on solutions can be challenging. When there are various people involved, they may have their own biased reasons or biases about what the solution should be. Remember that your responsibility in solving a problem and critically thinking is to explore from all angles and not just one. Part of agreeing on solutions involves conveying information that shares a solution for best for the organization that does solve the problem and best for all involved. You may not be able to make everybody happy, but doing the right thing and the best thing is what your responsibility will be. And finally, the sixth step of this phase is to do a cost-benefit analysis. This will help you in ensuring that the solution that you are about to choose will be the best benefit from both a cost and practical perspective. So doing a cost-benefit analysis will help you in that decision-making process as well as selling the solution after the decision has been made to those who are in power. The next step is to introduce your solution. This is where you want to propose your solutions to the appropriate decision-makers. Again, if you think about what we just talked about, exploring everything, interpreting your data, doing a cost-benefit analysis, all of those steps as you're exploring solutions will help you to present the solution in the best light. It prepares you for successful proposal of your solution to the decision-makers because you can give them all of the data that they could possibly need to support the solution that you are proposing by analyzing and interpreting your data, you can back up your solution proposal with all of the cost-benefit, all of the solutions that you explored, and why the one that you're proposing is the right one. When your decision-makers help you to make that decision and move forward with that decision, you can evaluate and revise accordingly. They may share information with you that changes your decision. They may be able to help support something in that decision or that solution that maybe need to be revised. All the information your decision-makers give you will help you in the evaluating and revising of the solution so that you are moving forward with the best solution possible for both the problem and the organization as a whole. Now let's talk a little bit about individual critically thinking. As an individual, being a critical thinker is going to be a huge skill because it will allow you to solve problems on your own. But there are appropriate times for individual critical thinking or individual problem solving. If the problem only has one answer that can be reached more quickly and effectively by one individual, that's when individual critical thinking should take place. Meaning, the problem exists, it needs to be solved immediately, and it really only has one answer. Then one person can make the decision quickly and move forward. There's no need for others to get involved or understand all of the details and be hugely committed to the decision or the solution. So individual critical thinking should only take place when it's appropriate and best for a single individual to solve the problem quickly and when there is one answer. Let's think about when critical thinking should take place in a collective effort. We would define this as group problem solving and it's a technique best employed when there's no straightforward or single answer. If you have a problem that doesn't have a single answer, there might be a variety of different answers, then it's good to get a group together to explore this. It's also best employed when the problem concerns multiple people. If the problem affects a multitude of people, then you definitely want to have that group together to share in ideas and discuss how it impacts them so that you're pulling together the best information and the best data that you can then interpret and evaluate to make the right decisions. It's also best employed whenever more than one person is committed to achieving the solution. Imagine that if there is a group of individuals who is faced with a problem and that problem impacts all of them and they all have different perspectives, but they all do want a solution. Then this is presenting the problem to a group, getting input from the group and it creates a win-win situation for everybody involved because of the fact that everyone wants the solution and by involving them and gaining their input and interpreting data with them, everyone will support it. It may be more heavy on the side of pulling everybody together, interpreting the data, gathering the data, but it can happen swifter on the solution side because everybody wants a win-win and everybody will support it and move it forward quickly. There are some business trends in critical thinking that support or encourage group problem solving. And here are the three examples of business trends. First there is process improvement. Whenever we look at process improvement, this is a process of an organization would look at their processes in-house and seek out ways to improve those processes. Well, that's something that encourages a group problem solving effort because a group is involved in the process, not just one person. And so getting a multitude of people together to explore the process and look for gaps or look for ways that it can be made more effective or more efficient together is a trend in businesses. Another business trend is internal empowerment. What we mean by internal empowerment is that many businesses will empower their employees to seek out problems and improve or fix those problems quickly. And so personal empowerment in an organization and being an internal employee who is empowered to fix problems can be very motivating. Businesses enjoy having individuals who know that they're empowered when they see a problem to gather the folks together who are faced with that problem and to work together to solve it quickly, effectively, and efficiently. And then there's continuous overall improvement, much like the process improvement. Continuous overall improvement is not a one-time process examination and improvement, but it's a continuous improvement where individuals are continuously seeking out opportunities to improve the overall organization and its processes. When we look at continuous overall improvement, everyone in the organization has the mindset that they are to work together to discover problems and continuously, completely fix them. In exploring process improvement, this is something that will regulate the flow of work that passes from internal suppliers to internal customers. So let's take a look at what we mean by that. It's going to require various departments from an organization to participate and work together to manage these processes effectively. Think about inside an organization, maybe a process of a order coming into the door and having to be processed from customer service, possibly to the logistics or to the service department, and then on to the invoicing and billing department. That process of paperwork and fulfillment and billing might be the process that is being examined for improvement. It would require individuals from the customer service side, potentially the sales side who interacts with the customers, also from individuals who are responsible for fulfilling the order and logistics, as well as your team who does the billing and finance as they receive the money in. Now, multiple departments would be involved in this process improvement. And what process improvement does is explore every step of the way and understand if there are any hiccups or stops or problems. If it's faced by one department, chances are other departments may be affected, and they may have to change their processes to ensure that that problem is eliminated. If one department solves the problem, it could cause a problem for one of the other departments. So this process improvement, a one time, one problem fix, requires individuals from various departments to participate in managing the process and exploring the process so that it is managed effectively and efficiently and improved for all departments, not just one. When we explore further into internal empowerment, now we have internal employees who are active and skilled in involving all employees for improvement activities. What this basically means is that employees are encouraged to be self-managed, that as they're performing their tasks and they run across a problem or run across something that may not be as efficient as it should be, they don't have to stop the process and gather everybody. They're encouraged to self-manage and actively seek out the solution to the problem. They're also recognized as skilled enough to recognize that other departments may be affected. And so they are to individually go and seek out participation from other departments that may be affected to fix the problem. Or they are to solve the problem and communicate that to the other departments. This is very effective in organizations where the tasks that are performed by skilled individuals are not across the board or interdepartmental. So maybe it might be an individual within one department sees a policy that only affects one department, that there may be a problem, they fix it, and they communicate it to their team. Internal empowerment, as I mentioned, as a business trend is incredibly inspiring and motivating. Individuals who are highly skilled and active in their work and in their teams enjoy being empowered to fix problems as they see them and communicate with their teams to solving the problems because it allows them to not have to wait or stop and they can be more productive. A very large business trend is continuous overall improvement. It blends the first two that we talked about, the process improvement and the internal empowerment. The reason this has become such a huge trend is because business today, as it forces folks to do more with less, is working towards continuous improvement as a necessity because our products have become more sophisticated. So organizations who are producing products are not, they're not in a position to stop producing their products to do a process improvement. If we practice continuous overall improvement, those products can continue to be produced and individuals are empowered to find challenges or problems and continuously seek out ways to improve it along the way. Customers expect that their products and their services will be received on time and faster than ever. So the expectation from customers have risen to the point where continuous improvement overall is necessity so that customer expectations are not dropped while an organization is seeking out to improve their processes. It's also a very big trend and a necessity in business because of the evolution of competition. If an organization wants to stay one step ahead of the competition, then it's important that they're continuously seeking out challenges and problems along the way and that their employees are empowered to not just discover them but to completely fix them right on the fly with their teams along the way so that they can stay one step ahead of the competition. And it also impacts the company's success. If an organization is not implementing continuous overall improvement and employees are not seeking out ways to improve an overall process, that company can see a decline in their success and they're not staying ahead of the competition. So it's a necessity, especially when a company's success declines and if they don't practice it, it surely will. Critical thinking requires us to obtain the right state of mind. Let's take a moment to think about what this means. When we are trying to solve a problem or we're thinking about critically solving or strategies around critically solving problems, there's a few things that we have to set our minds to. The first thing is we have to focus on the main goal. As I stated earlier, when we discover a challenge or a problem, the problem also involves people. And so we have to focus on the main goal. The main goal is to solve the problem. That often requires us to separate the people from the problem and not abandon the people, but to certainly focus on the main goal of solving the problem. It also requires us to consider that the main goal of solving a problem involves what is best for the organization and as a whole will support the organizational goals. That can often mean that we're not going to make everybody happy, but focusing on the main goal of solving the problem in the best manner for the organization is one of the states of mind that we must have whenever we are putting forth a critical thinking strategy. Another state of mind that we have to adopt is to avoid assumptions. We can't assume anything about the problem until we have done our investigation and gathered all of the facts and interpreted the data and explored everything as a whole. One of the big challenges of solving problems is to jump to conclusions or make a hasty decision without all of the facts being explored. And so avoiding any assumptions, in that state of mind, you will resist any initial thoughts of how to solve this problem until you can gather all of the facts. Another state of mind that is very important whenever you're employing a strategy for critical thinking is to refrain from blaming. Shifting or sending blame or pointing blame at somebody is not going to get you to the end result of solving the problem. It's often important to find out the causal effect, but blaming somebody is not gonna work. It's not going to help you to fix it. If you identify that an individual is the source of a problem, blaming them is not educating them. Taking time to share with them the opportunity to fix the problem and allowing them to provide input is a much more effective way to move forward in a critical thinking strategy than blaming them for the problem. Another state of mind that you will wanna employ whenever you're thinking critically is to aim for win-win solutions. This goes hand in hand with the refraining from blaming. When you strive for a win-win solution, you will find that others are involved and want to be involved because you are seeking out the opportunity to make this a solution that is a win for the organization and a win for the individuals involved. Sometimes this requires some savviness because an individual may not see it as self-serving, but if they can see it as a solution that is the best solution for the organization as a whole, typically, they will buy in.


I'm here with John Maddox from Nomad and John, welcome to the iZone. Thank you very much. Pleasure to be here. And can you tell us a little bit about what you're showcasing here? Yes, I'd love to. We are introducing a brand new technology at this show. It's never been introduced before, and it is an overlay for a cell phone, for a consumer product cell phone, that reduces the reflections by 85 percent, okay? And what you're seeing here, the phone on your right is your phone, like what everyone has. That's with an overlay, a plastic overlay or not, the phone on your left has been enhanced. We felt there was no, even a product category for this, so we started a whole new product category and we called it an enhancer, okay? It's a cell phone enhancer, and what it does is it's a very, so one of the keys is durability. Very challenging to come up with a durable coating for a cell phone, right? So it's not a moth eye effect or anything like that. It's a true six-layer precision optics grade AR coating that is put on a standard PET overlay, and then we have an anti-smudge on top of it. So it's really exciting, it's a lot of fun. Not only does it improve, it does several things. It makes your phone easier to see in the daylight, as you can see here, this is simulated daylight. Not only does it not anti-reflect the light that's coming from the outside, it doesn't reflect the light coming from the inside, so your phone is actually 4% brighter than it normally would be. Okay, excellent. Isn't that neat? That's excellent. And then the early advantage of it is that we have, here's a graph, this is your phone or normal glass plastic. These are the iPads that are out there that have AR coatings on them. This is what we're doing. So you can see it's dramatically better, and importantly, this over here is in the blue. High-energy blue light is very stressful on your eye, and what they go at night mode, they cut back because it doesn't let you sleep. You can see here, we're way down below in the blue, and even the iPads are actually even higher than screen glass. I see a big difference, especially starting with the visible spectrum, you have a dramatic difference compared to anything else that's out in the marketplace, is that fair to say? And this is a brand new product we're introducing at this display week, never been seen before in the entire world, nothing's been out there, right? And in fact, this is so early, we're not even going to be having or selling our web sales until next month. So people that are at the show, we're giving away overlays for free on selected phones. Okay, excellent. I have to stop by and get one, too, for my phone. What kind of phone do you have? This looks pretty neat. iPhone 7. We got it right here. We can give you an overlay, and then this will be available to the public on nomad.com in about a month. Excellent. So just one last question on it. Can you tell us briefly about how the technology works? What have you done differently that makes this much better than anything else that's out there? Okay, well the key to AR technology, the reason it's not out there is durability. So people have been able to make AR coatings for years. So on your beautiful Nikon camera, there's that green coating on the lens that you take care of, right there on that lens, takes care of so well with the little tissue, it's not durable. So you have, they are there, they're out there. What we've done is we have a new coating technology that's called, it's a PECVD. It's something that we invented about 10 years ago, and we've been bringing this to market, and we finally, instead of trying to sell the technology, we thought, you know what, it's a challenge to sell brand new technology, we're going to bring it to the consumer ourselves. So we chose, you know, to, instead of trying to sell machines to do the coating, which we have done honestly, but not for this, but we're taking this to the consumer directly with our own, really showing it off, what it can really do. Excellent, excellent. Thank you very much, John. John, it was a pleasure. Thank you. Thank you very much. Thank you. Very good.


and I believe that we are officially live. Hello everybody and welcome back to another seminar of our Sussex Vision Seminar Series as always with the Worldwide Neuroinitiative. I'm George Caffetzis, I'm a graduate from Tomas Oilers Lab and currently a PhD student with Tom Baddett. And that's your thought for today. I would like to once again begin by thanking Tim Vogels and Panos Bozellos for putting forward these seven expanding initially towards a greener and much more accessible seminar board. Having said that, allow me of course to get back to the reason we all gathered here for today and to introduce our guest from University of Manchester and the director of the Center for Biological Timing that is located there, Professor Robert Lucas. For lunch he's a bachelor degree in Biological Sciences from the University of York. Rob worked with Andrew Loudon at the Zoological Society of London for his PhD on Circadian Control of the Neuroendocrine Axis. During his postdoctoral years he worked with Russell Foster at the Imperial with an ever-increasing focus on Circadian rhythms and in 2000 he started as a lecturer at Imperial before joining the University of Manchester in 2003 where he has remained ever since and nowadays holding the title of Professor of Neuroscience. For a couple of decades now in his lab Rob has been exploring the general principles that govern the biological impact of light. From the retina and the at least traditionally believed as non-image forming light responses to an organismal level and namely how light regulates mammalian behavioural physiology. Furthermore, work of theirs includes the acycoblian characterization of light's effective intensity and the study of different options with both research and clinical perspectives. And having said that I'm very happy to be leaving the stage for him for a talk entitled Melanopsis Contributions to Vision in Mice and Man. So without any further ado from my side please all welcome Professor Lucas. Rob, the stage is officially all yours. Thank you very much George. Let me share my screen. You can tell me whether that's working. And then let's do it. And now, yes, is that happening? Looking good? I can see your pointer, so we are good to go. Perfect, thanks very much. Thanks for that interaction, George, and for inviting me to present on this series. I'm really looking forward to it. I've been an attendee a lot of these. So it's a great initiative. And congratulations on scheduling this between and the hour between World Cup matches. So that's great too. Thanks very much. So as George said, we've been interested in melanopsis and kind of unconventional influences on visual and non-visual functions for a while. And it's shockingly, what, nearly 25 years since we knew that the mammalian retina had photoreceptors other than rods and cones and around about 20 years since we knew that that could be explained by these neurons here shown in an on-fast view of the mouse retina, intrinsically photosensitive retinal ganglion cells expressing the photopigment melanopsin. And the story I'm gonna talk about today is something that we've been working on over the last while nearly decade, trying to understand where the and how melanopsin might contribute directly to form vision. And just a couple of kind of caveats at the beginning. Obviously there's something other people have been working on as well, but I don't have time to review that. So it's really gonna be summarizing our own data on this topic. But I think what I'm gonna tell you the take-ons are more or less consistent with what other people have found as well. Okay, so if you think about the function of melanopsin, one of the things to be aware of is that there aren't any simple answers, right? So if we ask what melanopsin is for, it was discovered of course in attempts to understand the mechanisms underlying circadian photoentrainment. So how the circadian clock is set to local time by light. And pretty soon thereafter, additional kind of end points for melanopsin were discovered in terms of regulation of the neuroendocrine axis and regulation of pupil size. And so there's an idea developing, first of all, that might be a circadian photoreceptor or if not a circadian photoreceptor, non-image-forming photoreceptor, and both of those kinds of terminology have some value. But there's an awkward truth here, which is that melanopsin knockout mice do just fine, right? So you can take melanopsin out of the system and they still have photoentrainment. They still have a pupil light reflex. Really, there's no visual function that they lack. So we can't designate melanopsin as responsible for any particular visual end point. And that makes sense if you think about how melanopsin sits within the overall structure of the visual system. So this is just a schematic of a retina, of a versatile retina. And where melanopsin lies of course is in a subset of these output neurons of the retinal ganglion cells. And those retinal ganglion cells then are capable of responding to light because they have melanopsin, some photopigment, but they're also responding to light because they have connections with the outer retina and therefore are downstream from signals coming from rods and cones. So at the very origin of the melanopsin light response, we have to think about it in relation to what's happening also from signals from rods and cones. There's no separating it, right? It's a unity, right? So then the other really interesting bit of melanopsin biology is that if you look at the IPRGC family, turns out there are multiple classes of IPRGCs and collectively they project to every retina or recipient region of the brain. So on the one hand, melanopsin does nothing because melanopsin knock out mice do just fine. On the other hand, maybe it does everything because IPRGCs go to everywhere. And that highlights, I think, a really important principle to keep in mind here, which is that we need to ask not what melanopsin does, but how melanopsin fits into the picture of vision involving also rod and cone photoreceptors. And to get to that question, we need to start by considering what are the sensory capacities of melanopsin and how might that compliment what rods and cones are capable of doing? Okay. So in terms of describing melanopsin's fundamental sensory properties, of course we have a problem, which is that unlike rods and cones where we could separate a rod or a cone photoreceptor and record its sensory, its light responses, IPRGCs sit there in the inner retina where they're supposed to be getting input from the rods and cones all the time. So if you record an IPRGC light response, it's a composite of melanopsin and rod cone influences. So how can we separate the component of that response that comes from melanopsin? And the most straightforward way of doing it and the way that's being used most widely is to get rid of the rod and cone signal. So we can do that using retinal degenerate or transgenic animals where we're silencing or getting rid of the rod and cone photoreceptors or by applying pharmacological agents which deaffer the IPRGCs in different ways. I'm gonna talk about for a little bit about the kind of the outcome of those sorts of experiments in different contexts. All right, so the first thing if you do that we can learn about the melanopsin sensory capacity, it's that it's maximally sensitive in the kind of cyan portion of the spectrum of the Lambda max about 480 nanometers. So this is really, really useful information but it doesn't really separate it with what rods and cones can do because that's right in the middle of the visible spectrum, okay. So one way in which it's different from rods and cones is if you look at rod-less comas animals or rod-less comas preparations, they're much less sensitive to light than an intact preparation. So the sort of threshold sensitivity of melanopsin is really pretty high. And so if you look at the pupil light reflex, you need about 15 lux of daylight to give the equivalent amount of photons for melanopsin to drive a pupil light reflex. So that gives you an idea of threshold. And then if you look at different responses you can have a slightly different answer. So for the circadian clock, for example, it's much less light. So 0.5 lux of equivalent daylight would give you that effect. So a couple of things from that, clearly far above threshold for rods or cone photoreceptors but equally far from ludicrous amounts of light. So most of us here as we watch the seminar will be having melanopsin activity. It's well within a kind of a dim light range. Okay. So one of the other cardinal features of it from rod-less comas preparations is that the signal has very, very poor temporal resolution. And so this is data from David Berson's description of IPRGC's way back in 2002 and showing that in response to a light step here at low light intensities it takes a long time for the IPRGC to start being activity, activated by its melanopsin signal and then it decays a long time afterwards. And once you get higher light intensities that on switches faster but you get an even slower decay thereafter. And we see that as well if you look in the brain. So this is a work from anesotized mice where we introduce a multi-electrode probe into the dorsal-electrogeniculate in rod-less comas animals. And you can find lots of light responses but again, they have this characteristic being slow to turn on and slow to turn off. So in terms of visual capacity then that implies that there's kind of a space-time averaging element to the melanopsin signal which would introduce kind of visual blur for visual images, for visual patterns. The other thing is that they have very poor contrast sensitivity. So in the rod-less comas animal we've tried quite a few times to look for light adapted responses with reasonable visual contrast and pretty much failed. So it's very hard, this is data for a sinusoidal modulation a very high amplitude sinusoidal modulation a range of frequencies. And you can see there's almost, there's really is no significant response from these rod-less comas animals. Okay. So the poor chamber resolution, poor contrast sensitivity is bad for many visual functions but of course for some things it's totally fine. And one of the functions for which it would be pretty good is measuring that change in ambient light in background irradiance. And in some ways then, if you don't need very high contrast sensitivity, in fact, maybe it's good not to have high contrast sensitivity because you need to track a very wide range of life intensities that might happen over a dawn or dusk, for example. And similarly sort of space-time averaging is quite useful for that because you can get a more accurate estimate of light intensity. And it's interesting that if you look at the threshold for menonopsin responses, they sort of start at civil twilight and it's carrying you all the way through then into that daylight range. So it's very good for that. Okay. So, but what I want to talk to you about is a manonopsin control contributions to vision and of course, that ability to measure background light intensity can be important for the visual system as well. And I'm not going to talk about this in detail, but I've already mentioned the pupil light reflex. And if you think about what manonopsin does for vision, certain pupil size is probably a really important first answer. But there's also growing evidence that manonopsin contributes to kind of a network light adaptation in the early visual system. So work from a number of labs around the world, not my own, have shown that IPRGCs make these centrifugal intra-retinal connections to send a signal out to the rest of the retina. And again, work from partly from my group, but also from others, showing that there's a manonopsin-dependent adjustment in the visual code. And I don't have time to talk about the lovely work of my friends and colleagues in Manchester contributed to this over the years. So what do I want to talk about? I'd like to talk about the work that we've done, asking the question of well and whether manonopsin itself could make a direct contribution to form vision. So why is that a question worth pursuing given what I've told you already? So first of all, we know that circadian light responses in humans can survive even in the absence of light perception. So we think that those responses come from manonopsins as work from Chuck Seiser's lab in the mid-90s. But we don't know, but we think it comes from manonopsin and yet these people have very, very rudimentary visual vision. So having manonopsin is not itself enough to have vision. On the other hand, there are a number of papers showing that visually guided behaviors can be recorded in animals that lack rod and cone function. That's either an advanced retinal degeneration or the work of Eckeren colleagues in genetically silenced rods and cones. So we've done some work with the retinal degeneration model in this. And I can tell you getting them to show visually guided behavior is very, very hard. They're pretty close to blind. So again, that fits in a way with human phenotype that manonopsin on its own is very, very bad at supporting vision. Echo got much better outcomes with her preparation, interestingly. And that maybe highlights something that we need to keep in mind when we ask questions about manonopsin function based on rod-less cone-less animals. And that is that this is a totally unphysiological preparation because manonopsin is always supposed to be working in the context of incoming signals from rods and cones. So as an example, it's perfectly tenable to think about manonopsin really as a neuromodulatory influence that's regulating those signals coming in from rods and cones rather than a source of independent visual information in itself. And obviously if you get rid of rods and cones, then it's a totally different way that the system's working. So could manonopsin sensory capacity be different if we looked at it in the intact retina? And that's a challenge that we've set out to look at some years ago. And the obvious problem we have is how do we separate the manonopsin signal from that coming from rods and cones in an intact retinal system without first of all kind of removing some of those inputs. And the strategy that we've taken is to take a concept that we borrowed from psychophysics, visual psychophysics and color science that that's a receptor sign substitution. So many of you will know about this. I don't have time to go into great detail but just in broad principles, this is how it works. So imagine that you have two photoreceptors in your visual system and they differ in their spectral sensitivity. So I've just plotted the spectral response profile for photoreceptor one and photoreceptor two. You can present a narrow band light source that will very actively stimulate both photoreceptor one and photoreceptor two. And you can also present a different stimulus that will very actively excite photoreceptor two but not photoreceptor one. And if you adjust the intensity and wavelength of those two lights, you can achieve a situation where they provide exactly the same excitation for photoreceptor two, but A is always going to be much more active, much brighter for photoreceptor one. And substituting light A for light B therefore is silent for photoreceptor two but represents a big increase in effective brightness for photoreceptor one. And the outcome is that you record responses elicited by photoreceptor one. This is a very robust phenomenon. It's the basis of RGB architectural visual displays for example. And we can expand it to three or more photoreceptors by adding spectrally distinct light bands. You can use it to allow independent control of effective brightness for any target photoreceptor alone and in combination. So it's very powerful. But one limitation or one of the limitations is it works best when photoreceptors have divergent spectral sensitivity. And that's why all of the mouse data that I'm going to show you use this really, really powerful model we got from Jeremy Nathan's lab which is an animal in which the human red cone opson is expressed in place of the mouse medium wavelength sensitive cone. So it shifts their cones in sensitivity away from melanopsin spectral sensitivity. The other really important thing here is that it's all about calibration. It's all about getting those A and B lights exactly the right wavelength and intensity combination.  They're in the published papers, but we do a lot of it. Okay, so how does it work? So this is work from Tim Brown when he was in my lab. Please say he's now a professor here at Manchester and a former speaker on this Sussex Visions seminar series. So what Tim did was to produce a system where we only have three types of LEDs. We have a UV, a blue and a green and we can independently control their intensity. So this shows the spectral power distribution of two of those lights at two settings where we're regulating the amount of blue light here so that when we're producing a lot of blue light that has a big stimulus for melanopsin. And to make sure that it's not also a stimulus for cone we adjust the red and the UV lights to compensate for the effect on cones. So we can produce a stimulus which is only visible to melanopsin. And we can have a control condition where we get exactly the same melanopsin stimulus but now we also allow cones to see an increase in light intensity by just having a spectrally neutral increase in light intensity. So what happens if you do that and you record from the mouse visual thalamus? And the answer is that your responses fall into two different response categories which we call melanopsin responsive or non-melanopsin responsive. And the melanopsin responsive units when you present an all photoreceptor stimulus have the sharp on excitation and then maintain firing when the light is present and then it decays afterwards. And when you do the melanopsin only signal you get this quite different sort of response where you first of all don't see a response and then it builds up slowly and dissipates slowly. Okay, whereas the non-melanopsin responsive units don't respond to the melanopsin only stimulus and only respond transiently when the light goes on. And we get them at a ratio of about one to two. So about a third of the units are melanopsin responsive. And of course we can check in melanopsin knockout mice whether to make sure that our stimuli work and again in melanopsin knockout mice we don't get a melanopsin only response. So in the dorsal atrogeniculate nucleus of mice sustained units are melonic to responsive and visually intact animals. The melanopsin component responses qualitatively distinct because it's sluggish and sustained. Okay. So having established that principle we've gone on to use it quite a lot. And one of the things we wanted to do was to develop a more sophisticated iteration of it. We wanted to add additional wavelength bands so that we can control rods as well to make sure that we weren't recording responses from rods at all. And then also allow us to present patterns stimuli. And Frank Marshall who's an excellent workshop technician developed this thing based on a DMD projector system where we swapped out the light engine and now can control, can present images with five different wavelengths of light. And Annette Allen is one of the heroes of my presentation. She was involved in this work and lots of what I'm going to talk about now. And it's now a Henry Dale fellow here in Manchester. So when you do this and present melanopsin only stimulus looks the same as when you do it just with a three LED system. But what we can now do is do more complicated things. And one of the things we wanted to do early on was to ask not what melanopsin only can do but what happens if we provide a stimulus which is visible to rods and cones but invisible to melanopsin. So because we have a different wavelength sensitivity to our cone photoreceptors when we flip from two different spectral compositions they look different color to us but for mice they will look the same for melanopsin but want to look brighter for rods and cones. And when you do that you see if you like the flip of the melanopsin only response. So at early points in that step response the response is exactly the same. And the longer that the step is present the more divergent those two conditions become. So firing is lower in the mel less condition. That requires quite high contrast for melanopsin. So just keep that in mind we need rather big differences of melanopsin for in order for us to see that distinction. And that's gone on to look at the frequency preference of that melanopsin signal by using this binary noise stimulus where we're introducing steps at between 15 and 0.1 Hertz and looking at a cross-power spectral density analysis you can see that for our MR units first of all they like low frequencies very much but in the mel less condition they like them less. And by contrast the non MR units don't particularly like low frequencies and there's no difference when we present the mel less condition. Okay. So melanopsin makes a unique contribution to DRGN activity and maintain response under extended presentation. So now we want to use the pattern stimulus element of the projector and we can do that now by introducing patterned images. So here we have a bar that's only visible to melanopsin and we can use that to map spatial receptive fields. So when we did this we were relatively agnostic given the time frames it's totally possible that melanopsin signal just appeared diffusely over all LGN neurons or a large fraction of LGN neurons and didn't really have any spatial was not conveying any spatial information but actually it turns out that you can map spatial receptive fields very well for the melanopsin only stimulus and they match the size and location of receptive fields to a simple bar stimulus for that unit. So the spatial information the spatial receptive field for melanopsin is exactly the same as it is for rodent cone photoreceptors for LGN units. Then we can ask what happens with those bars not visible to melanopsin. And again, if we compare the responses this is a representative unit for all photoreceptors where we get a nice when the bar appears here we get a nice on response which is then retained as long as the bar is present that's much less clear when you have the melanopsin less condition where this sustained activity is much reduced. And that means that if you map receptive fields you get different answers depending on well, you get different amplitudes depending on where you are in that 10 seconds of bar presentation. So at early points, the melanopsin less and the all photoreceptors response are superimposable whereas if you look at later time points then the amplitude of that receptive field is much smaller in the mel less condition. So melanopsin enhances spatial information under extended presentation. Okay. So what our electrophysiology has told us so far is that it's met you can there are measurable melanopic spatial receptive fields so it's feasible that melanopsin might contribute to the representation of spatial images in the LGN. And indeed it looks like melanopsin makes a distinct contribution to the visual response properties of the of neurons in the visual thalamus by enhancing response amplitude under extended view of higher contrast spatial patterns. So let's consider then why that might be useful for something more natural an active, you know, a natural viewing situation. And for that, I think we need to keep two things in mind about vision in about natural vision. The first is that natural scenes show strong correlations in local radiance. And the second is that there's an inverse relationship between the frequency and magnitude of head and eye movements across all species at least that we've looked at from the literature, including rodents. So what a net did then was to look at a simulation of what that might mean from the perspective of the receptor field of an individual DLGN unit viewing any random scenes. So this is a scene obviously of sky and ground with bushes in between. And what she's done here is superimpose the receptive field over time, the multiple placements of that receptor field across the image starting with the simulation where you've got small eye movements here or head or eye movements here which move the receptor field around this part of the visual scene. And then you have a big change and you have now the receptor field falls in the sky. But again, you have a more frequent lower amplitude changes in the direction of you which move the receptor field there. If you look then at what happens to the radiance of light within that receptive field what you find of course is that you've got through this phase here when you're mostly located here you've got lots of small amplitude changes in radiance. And then you get when you change your direction of view you get a big change in radiance and then you have an epoch here where there are smaller changes. So maybe then what melanopsin might be doing is not really tracking these small events here but helping keep track of what happens when you have these big changes here. In other words, the big patterns here between the ground and the sky in between eye movements. And that makes sense also when you think about the contrast sensitivity of melanopsin, of course the contrast when you look at analyzing the receptor field over time when you make big eye movements is much more biased towards high contrast than when you look at the between shifts and gaze epoch. Okay, so that's how it could work. Do we have any evidence that it does work that way? And to get at that what we did is ran a simple experiment where again we're recording from the LGN in mice and we envisage scenario like this, right? So this is our neighboring building here in Manchester but you can see how it's got patterns throughout but they differ across the scene in how bright the overall region is. So you have an area of high brightness, mid brightness and low brightness. So this is a very typical thing that might happen in visual scenes. So what we can do then is present to ironetitize mice the simulation of the eye moving to look at different parts of that scene by taking an image that has this characteristic and just changing its overall brightness. And we do that every one, five or 10 seconds. So to present a stimulus then that looks for the photoreceptiles like this. So all the time there are these high spatial frequency elements and throughout the recording Annette's shifting these a little bit to stimulate small eye movements. And then on top of that she's putting these changes, these shifts and changes of direction of view which are shown here then which give you big changes in radiance. And in this case because it's a spectral neutral change they're visible to all the photoreceptors. But of course we can do that. We can change the spectrum rather than the brightness and we can produce a vision that's not visible to melanopsin. So in terms of rods and cones that got these changes in background but melanopsin thinks it's exactly the same or conversely how something that's visible only to melanopsin but not visible to rods and cones. So the whole time there's this visual image and it's changing a little bit to simulate small eye movements. And at the same time we're changing it as if it was as if the eye was shifting to look at different scenes that were differing in brightness. Okay. So what happens when you look at the melanopsin responsive unit population in response to this stimulus. And if you look at the all photoreceptors trace here you can see that they're clearly responding to elements of the stimulus. And that's true also for the melanopsin less and for the melanopsin only but I think you can immediately see that neither of these conditions do as well as the all photoreceptors. And so what Annette did was simply look at the correlation coefficient between stimulus radiance or nominal radiance for the melanopsin less and melanopsin only condition and the firing way of neurons. And if you look at the rate look at the melanopsin responsive units you can see that that's much better for the all photoreceptors and pretty much equal for the melanopsin less and melanopsin only. So melanopsins required to have this good tracking of that stimulus. And even without rods and cones you can still get reasonable tracking. Conversely, if you look at the non-melanopsin responsive units first of all, they don't track these large sustained changes in radiance very well. And so you can compare this to this but also there's no effect of melanopsin. Okay. So we're gonna leave the mouse electrophysiology here but just to summarize what I've told you melanopsin compensates for relaxation of rod cone signals allowing a better representation of spatial patterns in brightness in the mouse DLGN within a reasonable framework for pattern vision. So what might we predict then if we wanted to move to recording visually evoked behaviors and to try and work out how melanopsin might contribute to visual behaviors? We expect that melanopsin could contribute to discriminating core spatial patterns and during periods of visual fixation. And so those are the predictions that we want to try and test by doing some assessments of vision. So how could we do that? So it is possible to record a melanopsin contribution to vision in visually intact mice.  There's a false choice here where they can swim to get to the escape platform and we train them to swim towards a brighter window to find that escape platform. So that's the training epoch. And then what we can do is change the wavelength of those two lights. So in our probe sessions, one lane is always red. So that's gonna be very bright for cones and moderately bright for melanopsin. And then we present as the alternative choice a green panel where we can alter its intensity. So the bias for melanopsin is always defined green, brighter than red. So we'll expect if melanopsin is relevant we'll expect them to have a bias towards swimming towards the green panel, right? And if we then plot the percentage at which the mice choose the green channel as a function of the brightness of that green panel no surprises that if the green panel is very bright then they reliably swim there. And if the green panel is very dim then they reliably swim towards the red. What's interesting is the point at which they judge those two panels to be equally bright is different in our red cone knock-in mice compared to red cone knock-in mice that lack the melanopsin gene. So that loss of melanopsin gene is changing the spectral sensitivity of their preference of their judgment of brightness which we think is pretty good evidence that the melanopsin is helping those mice to judge brightness in this paradigm. So it is possible then to find visual responses in mice that have a melanopsin signature it is also very, very hard work. It's hard work knowing how asking a mouse what it could see and we were lucky early on to establish a collaboration with Sichi Sugimura who's a psychophysicist who was doing similar work in humans. And so what Sichi has done here is generated as kind of a spot stimulus to spot a large spot stimulus. And he's asking people to judge relative brightness against a reference and a test stimulus and the test stimulus he can either add in melanopsin effect of brightness or not. And what he finds is that the point at which people judge those two stimuli as being equally bright. So that's that 50% point here is dependent on how much melanopsin content that the reference stimulus has. So evidence that in humans they judge large field light fields with higher melanopsin stimulation is brighter. And this is something that's been reproduced now many other labs and proper psychophysicists are looking at this and have looked at the relationship with luminance and exactly how it might fit into models of brightness perception. But what we wanted to do in view of what we had from the mouse data that was coming through was to move towards being able to present spatially structured stimuli to human subjects to look at how melanopsin might contribute to spatially structured vision. And generating a version of our melanopsin projector system for humans is difficult. And the strategy has to be slightly different for various reasons. But what we've done is again start with these data projectors, these projector systems. But in this case, we've taken two projectors and we superimpose their image and we filter the RGB channels of each of them so that instead of now having two images each of which have three channels RGB we now have two projectors each of which have three channels but of different wavelengths. And so we can end up with a system like this where we've got a band here in the deep blue something at cyan, something at green something at yellow, something at red. And that gives us the degrees of freedom then to modulate it selectively the melanopsin brightness of any pixel within that image. So here are two spectral power densities that are melanopsin high and melanopsin low and they appear identical in terms of hue, saturation and luminance. That's because they identical for cone photoreceptors. And again, this is to remind me that lots and lots and lots of calibration to make sure that this works particularly in humans not only between individuals but also between parts of the retina. It's very important that you keep that in mind. Okay, so one of the first things we'd like to do with that is just to present some melanopsin images and see what we see, right? And the answer is it's pretty weird but there's definitely something there. So this is a kind of a documentation a documentary description of our sort of subjective experience. So what we've done here is present two versions of a standard image here. And in all cases we ask people to fixate here and we fill out this kind of central region of the image. Happy to explain why questions. And then image one doesn't, it's not just has the sort of standard melanopic contrast between elements of the image. And image two is augmented for melanopsin contrast. So the bright bits of the image look really bright for melanopsin and the dim bits look very dim. But for combs, they're exactly identical. So photometrically, these are identical images. And when you present them to people, this is like free-form descriptions of what people say. And it's a sort of a sense of them being brighter but more distinct, more sort of stand out. And then if you ask people to rate which of those versions is more distinct, they reliably report that the high melanopic image is more distinct. So consistent with our view then that there's something about patterns with this stimulus that melanopsin is revealing. Okay. I think I'm gonna whiz through this just to say that one of the other things you can do with this melanopic stimulus is you can ask whether it regulates sort of circadian and non-visual functions as well. And so we worked with Christian Kajoken at the University of Basel and had people going into his lab in the evenings just watching movies either in melanopsin, lower melanopsin, high condition. And as over the course of the evening people tend to become more sleepy but they became less sleepy when the movie was rendered in melanopsin high. So augmenting melanopsin was keeping them more awake and also it was tended to suppress their melatonin production. So the device can show that the control of melanopsin can be used to adjust the impact of long-term light exposure on sleep alertness and melaton expression. But let's return to our question of form vision and what Annette went to go on to do next was to present more kind of calibrated stimuli to ask what sort of thing that humans might be able to see if we're in melanopsin. So for these first experiment, what she's done is again had a fixation point here and then somewhere in the periphery, we put this grating and that grating can exist in one of four directions, four orientations. And we asked the subjects to tell us what orientation that grating was, okay? This grating is visible only for melanopsin. So as far as the cones are concerned, this is just a continuation of the background field here. So it's a melanopsin only stimulus. And when you do that and you ask people whether they can see it, people get significantly better than chance at judging the angle here of this grating. On the other hand, you can see here that at no point are they getting at 100% correct. So it's not easy to see these things. So it's more of this feeling that there's something there. Okay, so the next thing we can do is we can change the grating frequency and ask what happens to their ability to see that. And when you do that, you can see that really we need pretty fat bars, pretty thick gratings in order for people to be able to resolve that melanopsin only stimulus. So it's only when we have very low spatial frequencies that we can see that stimulus. As a control, we can do exactly the same thing for an all photoreceptor stimulus and that has a much more familiar spatial frequency preference where you get optimal performance here about one or two cycles per degree. So one last thing we can do here or one of the other things we can do here is adjust the contrast, the melanopic contrast of this grating. So not just have it at maximum contrast but start to try to break it down. And what you see is that you need relatively high contrast stimuli in order for this to be visible. Whereas in the orange here for an all photoreceptor stimulus, I mean, basically we run out of resolution for our projector. Any all photoreceptor stimulus at the lowest contrast we can present is visible to the subject. So it's much less contrast sensitive than the rodent cone system. And that if you remember makes sense, right? Because if we looked at our simulations of natural view of visual scenes, we're expecting first of all that melanopsin is gonna be doing is gonna be particularly useful for low spatial frequency patterns and also that it can be biased towards higher contrasts. Sorry, lower contrasts. Okay, so melanopsin only patterns are discernible at low spatial frequency and high contrast. So the last work we've done on this is a work from Tom Boulders in the lab. So Tom's been working on this troxylaphating paradigm which relates to the question of how melanopsin works under extended view. So some of you will be already familiar, I'm sure with this visual illusion. So what we need to do here is focus is stare at this man in the boat but keep attending to the sun here. And this is a painting from Claude Monet. And this is a phenomenon that was first described actually or first documented by Erasmus Darwin. And what it is is you should start seeing that the sun start fading away, so you stop seeing it. And this is the troxylphating. So the fading of elements of the scene which are under steady view. So if we think about what we asked, what we thought melanopsin might do based on the electrophysiology, this is the type of visual illusion where we might start seeing a melanopsin contribution, right? We might think that having more melanopsin would delay that troxylphating event. And so Tom's looked at that by presenting a stimuli such as this. So again, we have a fixation point here and this time in the periphery, we get this kind of fuzzy blob appearing in the periphery. Yeah, it's a bright blob. And we just ask people to fixate on that and tell us when that blob disappears. And the answer is that the rate at which that blob disappears is dependent on how bright the spot is, right? So if you increase the contrast, the luminance contrast on the spot takes longer for the spot to disappear. Now we can introduce the melanopsin dimension and take a spot which has the same luminance contrast but introduce melanopsin contrast. And we find reliably that the spot takes longer to disappear. There's quite a lot of inter-individual variations. So in some ways it's easier to see it as a Z-score and you can see here that for each individual there's quite a substantial difference in the duration that spot lasts if it has a melanopsin component. So it works for bright spots, it also works for dark spots. So this is the converse stimulus where we're asking people to tell us when this dim spot disappears. And again, that depends on the contrast between the background and the dark spot and adding melanopsin contrast to that has the expected effect. So again, it takes longer for the spot to disappear if we have a melanopsin contrast component. Okay. So introducing melanopsin contrast slows image fade. So that's really what I wanted to tell you and to put it together in terms of like linking I think what we see in terms of the mouse electrophysiology and the human visual test, visual experiments. I think we can type think about a visual scene such as this as having patterns over multiple spatial scales, right? So from the very fine detail here to ultimately to just the overall amount of light in the environment with everything in between. And what we find is that once the further you move into the low spatial temporal frequency range the more that it looks like melanopsin is important. And that melanopsin does seem to make a distinct and uncompensatable contribution to the representation of these lower spatial frequency elements of the image. So you can almost think about it as melanopsin allowing cones to focus on the very high frequency elements here by taking care of the lower frequency components and allowing us to have visual fixation by allowing us to by keeping track of the course patterns while we're fixating on small elements here, okay. So what else is interesting to do here? I mean, there's so many things but just a couple of things that I think are really cool to be thinking about. One of which is I think that we still need to test the limits of this model in different scenarios looking at different species, for example but also in different types of view. So I think that's really important. The other thing I think to keep in mind here is that we're really asking melanopsin to do a lot of heavy lifting, right? Because if we talk about temporal scales we think that melanopsin is important in telling the difference between day and night. So that's a really long timeframe. Maybe even times of year, a really, really long timeframe. At the same time, it's also contributing to those differences in brightness that occur within the timeframe of shifts in visual, in gaze, in gaze across the visual field which is much shorter. It's also asking it to cover a massive differences in brightness between day and night time or across that dust to daytime transition and also the much smaller things that happen within a scene. So it's really, it's doing a lot and it'd be really nice to start relating that to the cell physiology and emerging evidence of signaling complexity for melanopsin. So this is a summary of what we know about the IPRGC population from Contreras et al in a very recent review and the upshot is that at least in mice there's probably six types of melanopsin methaml ganglion cell and they had distinct projections and distinct physiology. Really nice to start relating that more directly into their role to covering this range the spacia temple range of vision to which melanopsin might contribute. We also have surprising complexity in the signaling of melanopsin within the cell. So melanopsin is a G protein coupled receptor, right? Light activated GPCR like rodent conosins and it was thought for a long time that it was activating a G alpha Q signaling cascade much as happens in invertebrate receptor receptors. And that certainly is the case but we've shown in cell culture that melanopsin can also very efficiently activate G alpha I and G alpha S. And we know from the work from Tiffany Schmitz group and from King Waiow's group that actually you can get melanopsin signaling without G alpha Q pathways. So it'd be really interesting to think about how this signaling complexity also fits into this question of how melanopsin can cover this big spacia temple range. Returning to melanopsin modulatory influence on vision I think is also a really nice thing. So how is the visual code changing according to that melanopsin signal?  So just disclosure of interest. We have some patterns about designing melanopsin displays but leaving that aside, all of our visual displays and image capture architecture at the moment assumes that everything about vision can be encompassed in our three cone photoreceptor system. That's why we have RGB displays. If you're building a new type of visual display architecture it seems crazy not to also include melanopsin, right? So I'll finish with acknowledgements. We've been very lucky to get funding from the ERC the Welcome Trust and the BBSRC. I've mentioned some of the contributions from people in my group in Manchester while I've been speaking but it's really a massive team effort and all of these people have made big contributions as have our collaborators around the world. So thank you very much for your attention. Thank you very much Rob for this very interesting talk and your attempts to elucidate what is the contribution of melanopsin in vision in natural retina impact-wise when it comes to the input and naturalistic settings with what you try to take it like experimental-wise. There are already some questions appearing in the chat and I would like to remind to our audience that they can either post their question there that will moderate and communicate it to Rob or you can join us in the Zoom room that we are currently using and I will be posting the link right now in the chat because in five to 10 minutes depending on the question I will be terminating the broadcast and we will continue offline. So the first question is from Gregor Belusic. A high and great word. Maybe I've missed it, but how can you distinguish between human melanopsin vision and the possible effect of rod vision? Do you assume rods are saturated that they use light levels? Yeah, so that's a really good point. So in this, whereas in the mouse for our electrophysiology we have enough capacity to have stimuli which are also rod silent. For the human work we have we also, we're working at a light level where we hope the rods are approaching saturation and we realize that this is imperfect at least for the visual display work that we've done you can of course have stimuli which would also be rod silent but then you have very little contrast. So I'm sorry, melanopsin contrast. So it's almost like we put it together as the way that we think about it I suppose is that the work from the mouse poses hypotheses and those hypotheses we can then, we can then test for the human experiments but it's a sort of a conceptual justification that rods will make little contribution rather than a direct demonstration of that. So that's totally a fair question. Thank you. And the other question is from Wei Li is M4 the main conduit for melanosis contribution to form vision? So I think that's a great question, right? And I think that, you know, I think what's really important is to keep in mind is that what we're doing is looking at a systems level. So for us, we're totally agnostic about where this comes from in terms of the, in terms of the, in terms of the melanopsin response. What we can say is that, you know, we're seeing a melanopsin contribution in the mouse LGN to maybe a third of the LGN units. And obviously the M4 IPRGCs are a much smaller fraction of the total ganglion cell population. So at some level, we need to explain that discrepancy, right? And we don't have an explanation for that yet. So does that mean that those M4 cells have lots of projections that it's a massive expansion or that maybe some of the other IPRGC types of contributing and how that whole thing fits together? In terms of the phenomena that we've described, we don't yet have a clear link to an individual IPRGC type. I mean, in terms of projections to the LGN, it's not only the M4s that go there. So it's definitely possible that other melanopsin classes could contribute. And before I move on with the cross species questions and what expectations do they generate, like your findings generate or justify for different diets, some questions that I have, like if I really apologize, my ignorance, but when it comes to primate vision and retina, do we know anything about the density of IPRGCs with increased eccentricity? Yeah, so there's really nice work done by several groups. And from memory, the upshot is that the outside the actual fovea itself, the fraction of melanopsin positive retinal ganglion cells sort of remains relatively constant. So that means that there are many more melanopsin retinal ganglion cells in the kind of periphovial region and then as you move outside, but that reflects the ovial number of ganglion cells in those different parts of the retinal. And the other question I had like stimulus wise, because you present this creating that this invisible to rods and cones, but melanopsin cells can see, is it possible to like slightly move this creating, like to introduce a temporal aspect to the stimulus without the rods and cones seeing it or this is impossible? Sure, no, no, definitely, absolutely. It's possible to do that. Yeah, you can do that. Yeah, you can do that. Have you tried to see how the responses of the melanopsin cells might change? So let me think. So you're looking for a temporal modulation. I mean, obviously with the receptive field mapping stimulus, you know, this is the bar moving in space over time along the azimuth. So that sort of does that answer your question or are you looking for something? It could be, I'm just interested because like, I mean, and these are questions that I will try to ask later, but like because it looks like the melanopsin cells have like very long glantensis compared to what you would expect from rod and cone input. I was wondering what temporal frequencies they can encode when they are the only ones taking it. Yeah, so that would be, I guess the way that we approached that was with that binary modulation stimulus where we varied the frequency of that and it looked like and from that we estimate that frequencies like less than one hertz is when you start seeing a melanopsin contribution. But I think actually there's more to do without because that's not the same thing as a kind of a sinusoidal modulation, for example, modulation and that's something that we're kind of working on at the moment. So I can't give you an answer to that. Great, thank you very much. And like now I will proceed with the questions that Tom posted and if there are no more questions appearing from the audience after these two and the answers from you, I will terminate the live broadcast as we will continue offline and some people are already here. So the first question that Tom asks is, so in that view doesn't this imply that melanopsin should be relatively more important, the smaller the eye and that's the word, the special resolution. What about animals with tiny eyes? Right, well, so there's a whole visual ecology question built in here as well, isn't there, in terms of what's important about vision. And the reason that I say that is the extent to which we looked at cross species with this in terms of electrophysiology is we've been working with a raptomus which is a diurnal rodent that has a cone rich retina really massively expanded visual system. And for them, melanopsin seems to first blush much less important for vision. And that's probably because they're performing different types of visual tasks to lab mouths. So I think that would probably be the bigger determinant of how important melanopsin is. But and then so it's to do with how probably to do as much in terms of the spatial domain, the temporal domain, right? How much having that image stabilization vision is important for them, I would guess. So but really, really interesting things about how it varies. You know, that's one of the things I wanted to get across with is like probing this hypothesis with different species, I think is really, it's really a cool thing. And the other question of his, which takes into like takes it into more evolutionary context. So many normal mammals have had melanopsin in earlier retinal neurons, including before the on of split. Would one therefore expect of melanopsin signals and what would they mean? Um, I mean, in principle, well, blimey, that's that's a first of all, that's a very difficult question because it's pure speculation, right? But I think, you know, if you look at melanopsin outside mammals and you go into into number million vertebrates, first of all, it fits in the picture of lots of different types of of options, right? Not just melanopsin, not just one type of melanopsins, multiple types of malopsins. When you get into fish, I don't need to tell you guys. And then pinopsins and para-pinopsins and VA options and like to pick the bones out of that because presumably they're all doing something slightly different in terms of the sensory capacity of the fish. I would imagine, given that, you know, why does what is it about melanopsin that means that it imposes a relatively low sensitivity? So it's pigment density is much lower than rods and cones. So we're all going to have relatively low sensitivity and or low spatial temporal resolution. So you think that melanopsin is going to be doing that wherever it is and if that's in off bipolar cells, it's doing that for off bipolar cells, you know? So like it's an unsatisfactory answer, isn't it? I don't know. I mean, we will see Thomas here. So hopefully she will elaborate and continue down that road soon. So the last question that I have before we terminate the broadcast and continue offline is if I remember correctly, from my retinal lecture, so the melanopsin is a bi-stable option, right? So it can. OK. And that is, anyway, carry on. This helps with evading saturation, I guess, but it doesn't help with the latency, right? So the latency is dependent on the later biochemical pathway. Yeah, the fact that we have like this maintained response of an extended stimulus presentation could be just that the melanopsin signaling kicks in later. So this is why it gives the impression of. I say made like maintained in that sense. So Michael Doe, of course, and Harvard has done lots of really interesting work on this. So I'll just try and channel that. And I hope I don't mess it up. But the I think the the maintained activity then is to do with. Well, we know that melanopsin can be switched on and off with light. The rate of that happens at the light intensities we're talking about, I would argue, is relatively small because there's another thing that definitely happens, which is melanopsin has a dark regeneration. So that's definitely. OK. And it also has a biochemical signal termination. So first, Robinson has shown very nicely that you get phosphorylation of the melanopsin C terminus, and that's important for switching it off. So I think this ability, this bi-stability, tri-stability is a really important phenomenon and feature of melanopsin. But probably the things that we're talking about, it's you can think about it much more like a conventional photoreceptor that the rate at which it switches on and switches off is to do with the buildup of the second messenger systems and the rate at which the the the the the signaling cascade switches turns off and turns down again, scales up and down. I see. Thank you very much, Rob. And thank you in general for giving this this talk. And at this point, I will stop the live broadcast so we can continue offline with people that are interested. Thank you very much. My pleasure.