Welcome everyone to our Grand Rounds. A few of the Zoom ground rules in this particular Grand Rounds. If you'd like to be unmuted, please raise your hand or you can ask questions in the chat. Dr. Kramer will be monitoring that chat. If there's anything kind of timely for the topic that you're speaking on at that moment, would you prefer to be interrupted or save questions until the end? It is fine to interrupt me. Hopefully I'll notice. I'll be looking at the slides and I'm not sure I'll... Very good. And I did not, perfect. Thank you. All right. Well, I will do a brief introduction. So my name is Jeff Petty. I'm the vice chair of education. I'm in charge of our Grand Rounds series. We're honored to be joined today by Dr. Richard Kramer. He's a professor of neurobiology at UC Berkeley and where he's a professor in the Department of Molecular Cell Biology. And he's a CH and Anne Lee, Chair of Molecular Biology and Diseases and Director of the Vision Science Corps. Among his research interests, he really focuses on exploiting neuroplasticity to restore vision and retinal degenerative disease. There's certainly others in our department who could go on and wax eloquently on you and your accomplishments. But with that brief introduction to our clinical group, welcome and thank you for joining us. Well, thank you, Jeff. I originally was supposed to be in person there today and giving a research talk as well in the afternoon, but a couple of things intervene. First of all, I have a grant proposal due in about four days. Secondly, last week I came down with COVID. So it's just as well that I didn't come right now, but I'm recovered now.  So, yes, I'm gonna talk to you about sort of the most recent work that we've been doing in my lab. And this is gonna be much more sort of science than that is it. But let's see if I can share my screen. Is that, let's see, a second here. Trying to use just two screens and it's always complicated. Share screen, am I sharing? We do not see the screen. What do I need to do to share screen? And I'll just verify that you have the permission. Yeah, maybe that's the problem here. Is it showing the share screen in green? So there we go. I'm sorry, I see it now. How's it going? So. All right, we do see the screen. Audio is great. It's not present review. So we do see the sidebar. Now that's the wrong screen. I'll be right back to this in a second. In fact, I'm gonna close this screen. We do see suppressing retinoic acid just. Oh, you see that? Okay, great. Okay. I will now go to slide show late from start. So now you should see the whole screen and all its glory, correct? Yeah. It's great, perfect. So yes, I'm gonna talk to you about what might be a new idea for how to address the problem of vision loss and degenerative blindness.   Robert Mark and Brian Jones and their colleagues. So, you know, what happens is that in these disorders, rods and cones degenerate. People go through a stage where the outer segments of photoreceptors are largely missing. The vast majority of people in these diseases are stuck in this sort of middle situation where they've lost a lot of photoreceptors, but there are still some left and not completely gone. And then a small minority of cases, all their photoreceptors disappear and people lose all light perception. And it's these people that have been the target so far of new technologies that are intended to restore vision. And these technologies include things you all know about retinal implants, either positioned in front of the retina epiretinal implants or behind the retina subretinal implants. Of course, the epiretinal implant that's in clinical use is the Argus II made by Second Sight. And the subretinal implants are designed by a company called Pixium and they're still under clinical trials in Europe. So that's one approach. Another approach is to use optogenetic tools. Microbial opcins like channel rodopsin express them artificially in the downstream neurons of the retina to try to provoke light sensitivity in these cells. Of course, there's a huge effort by the National Eye Institute to develop stem cells to actually to regrow new photoreceptors and get them integrated into the circuit. And then finally, there's something that we've worked for 20 years on now, which are chemical, photoisomerizable chemical photo switches that get into neurons and impart light sensitivity on action potential firing. So all these approaches are really because they're all risky and also because they tend to supplant the activity of whatever rods and cones are left, they're really at this point restricted to people in this terminal sort of end stage degeneration population where people have no light perception. And that leaves behind this huge population of people that might be legally blind, have severe vision impairment either from RP or perhaps more locally for AMD that where the function cannot be restored. And those are the patients that we're primarily interested in. So I should say that to get these technologies to work, there's an assumption or there's at least the hope that the downstream retinal circuitry remains intact. Most importantly, the retinal ganglion cells have to remain connected to the brain and that the way it processes information needs to be more or less unchanged. And then if you put back light sensitivity you have some hope of restoring visual perception. But largely due to the work of people at Utah, we know that this isn't exactly the case. And so classic studies I mentioned by Brian Jones, more recently by Rebecca Pfeiffer as a student in his lab and Robert Mark have elucidated a process called remodeling. This takes several forms. First of all, there's the morphological aspects of this that you can see in animal models of retinitis pigmentosa. It develops slowly. So in mice, we're talking about at least six months after the photoreceptors have died. And in humans, we're probably talking about years or decades after the photoreceptors have died. You start to see sort of stereotypical changes in the structure of the retin. And there's a variety of changes that you see. One of the first things that you see is that some of the neurons, particularly bipolar cells, they lose their dendrites that formerly were contacting the rodent confotoreceptors. They start to sprout new branches of those dendrites. Some of the cells slowly start dying. Again, these are late events. The cells start to migrate out of their normal positions and beautiful lamina in the retina. And the entire retina can become disorganized and glial cells, particularly muller glial cells swell and they form a seal over the inner and outer margins of the retina. So these things, like I said, are happening late after photoreceptor death. But what has emerged more recently is the understanding that there are much more rapid physiological changes that start immediately as the photoreceptors are dying. And here's one big example of a physiological change. If you take a retina out of a mouse model of RP and you put it on a multi-electro-recording chambers that you can record from lots of retinal ganglion cells at once, here is the recording, extracellular recording of spikes from these ganglion cells. And this is spontaneous activity just with the retina in the dark. You could see that a wild-type retina, there's some spontaneous activity, but the retina that comes from this model of RP shows something like six to 10 times higher frequency of spontaneous firing. And so that's something that's been noted in mice and rats and dogs. And it probably is true in man that there's just hyperactivity of downstream neurons. And we've done a lot of work trying to understand what the basis, what the molecular mechanism of this hyperactivity is, and this involves single cell electrophysiology with patch clamping methods. And I'm not gonna go into the details here, but we see different kinds of ion channels that seem to be upregulated. We also have molecular evidence for this. So there are changes intrinsic to the retinal ganglion cells, there's also changes in other neurons in the retina that lead to this hyperactivity. And in addition, there's this rhythmicity that emerges from the degenerated retina. Again, when you record at sort of higher time scale, these are milliseconds instead of seconds, you can see that the spiking of these ganglion cells tends to occur in rhythmic bursts in the degenerated retina. And there tends to be synchrony across different cells. So somehow they're either being driven by a common input or they're linked up through gap junctions or both. And so all of these things you can imagine are, they're all happening as the retinal's degenerating. What if there's still some photoreceptors left? They're trying to get their message across. They've got a much more noisy background to get through, which includes this sort of rhythmic activity. And the idea is that this is gonna degrade the ability of the retina to encode information about light and dark, at least as long as there is still some photoreceptors. And this is an illustration of that, maybe more explicitly, here's a healthy retina, here's a bar of light that you shine on the retina, and here's a recording from one retinal ganglion cell. There's some spontaneous activity, but you can clearly see the light response above that activity, this retinal ganglion cell. But in a degenerated retina, where you have fewer photoreceptors, you also have this higher level of background activity. And now that background activity can obscure the light response. And so if we understood what it was that was causing this hyperactivity, maybe we could develop some kind of treatments that would suppress the hyperactivity and allow the light response to sort of reemerge. This isn't rescuing when I'm talking about a treatment that is preventing the degeneration itself. We're talking about something that is making the retina work better in the face of this signal corruption process. And that's really the theme of the entire talk. Trying to understand what causes this physiological remodeling and trying to do something about it. So the idea is that when the photoreceptors die, the question is how do the downstream neurons even know that the photoreceptors are dead? And I would say the prevailing idea until recently was that the synaptic signal that the photoreceptors are producing is sort of propagating through the neural circuit. And in the absence of that synaptic signal, there may be compensatory mechanisms that kick in in these downstream cells that change the way they operate. So for example, in the absence of an excitatory neural transmitter glutamate, maybe the downstream cells start to develop their own hyper excitatory activity to compensate for it. Maybe they also start to form aberrant excitatory synapses for the same reason. So that idea is called homeostatic plasticity. And we know that it operates in all neural circuits, but we do not think that that's what's responsible for the hyperactivity of the retina. And I'll, I'm raising the suspense level here. What is the degeneration signal that's causing hyperactivity? And I'm just gonna cut to the chase. And I'm gonna tell you that the hint for what this signal was, again, came from Robert Mark's lab. And there's a theme here. And the work of Brian Jones and his colleagues.  And he was talking about work that already was quite old at that point. And I guess the paper came out 10 years ago, but he was here maybe five or six years ago. And what they had found is that in one particular model of light induced retinal degeneration, this is a mouse that was particularly sensitive to light and exposure to bright light would cause the photoreceptors to die. They implicated retinoic acid as the signal that was causing these bipolar cells to sprout new dendrites. And this is just a diagram of cultured, you know, cell cultured bipolar cells that have been dissociated from the retina and applying exogenously retinoic acid, you can get them to grow new axons and new dendrites. They also had results showing you can block the sprouting of dendrites in this mouse model that I mentioned. So that got us thinking maybe the hyperactivity we see is also a consequence of retinal acid. And so before I start showing you some of the evidence that I should tell you how retinal acid is made and something about the retinal acid pathway, retinal acid is a downstream metabolite of vitamin A, also known as retinol. Of course vitamin A is critical for vision. It's sort of extracted from the bloodstream. It's processed in the retinal pigment epithelium, which have enzymes that convert vitamin A into retinaldehyde, including 11-cis retinal, the chromophore for opcins. And this retinaldehyde is normally absorbed to a great extent by the rod and cone and her segments. Each rod contains a hundred million copies of rhodopsin. So there's a very large sink for absorbing all of this retinaldehyde. And ordinarily there's sort of cycling between the retinaldehyde absorbed by the photoreceptors and vitamin A metabolites. But when the photoreceptor outer segments, particularly the rods, start to degenerate, now this gigantic sink for absorbing retinaldehyde starts to disappear. And even though the RPE down regulates how much it produces, there's still some retinaldehyde that escapes. There's also sort of a breaching of barriers in the retina. And the retinaldehyde can reach cells that express this enzyme called retinaldehyde dehydrogenase, which is a member of a big family of other aldehyde dehydrogenases, which I'll talk about in a few minutes. So, and what RAL-DH does is convert retinaldehyde into retinoc acid. So retinoc acid is a really important regulator of growth in embryonic development. It exists in gradients in the developing embryos. It sets up patterning of limb embryogenesis. So it's a really critical morphogen early on. But then the system is largely in most parts of the body, including the CNS, retinaldehyde acid and its effectors are down-regulated in adulthood. And the way this retinaldehyde acid works is by binding to a retinaldehyde receptor. Here it's RAR-alpha, which dimerizes with another protein called RXR. And this dimer binds to specific sequences in DNA and turns on gene transcription. So this is a transcriptional regulator that turns on programs of transcription in cells that it acts on. And so this is the system that we think is engaged as photoreceptors degenerate. And as there is an sort of an excessive amount of retinal gas. And so I'll show you some of the evidence for this. First of all, we can detect the higher retinalg acid induced gene expression in degenerated retinas. So we do this with a reporter construct. This is a gene that we introduce into retinal neurons with an AAV virus and the gene has two parts. First of all, I'll get to the business part of it first. First of all, there's GFP that's under the control of this retinalg acid response element. So if there's elevated retinalg acid that activates the receptor, the retinalg acid receptor and it turns on expression of GFP. And then there's another module in this gene which expresses red fluorescent protein and that's just constitutionally made. So that's just a let's us that's sort of a control that tells us which cells have been transduced by the virus and controls for the possibility that maybe normal and degenerating retina are of different susceptibility to be infected by viruses. So if we compare, for example, in mice, the wild type mouse retina versus a degenerated mouse retina, the virus infects cells equally in these two retinas but it's only in the degenerated mouse retina where we see GFP being expressed to a large extent. And this is even more dramatic in a rat model of retinitis pigmentosa. This is a truncation in rhodopsin itself which leads to the rods dying. And you can see once again, GFP is greatly upregulated. We're looking at the level of retinal ganglion cells. So this is expression of RA induced genes in the retinal ganglion cells. So there really is more retinal acid in these retinas and it's capable of inducing gene expression. And if we inhibit that retinal acid receptor, this is with a small molecule originally invented by Bristol Myers Squibb, BMS 493. If we inject that into the eye of one of these mice and the contralateral eye gets just saline, what we can see is that the, and it takes a few days for this to happen, but we can see the level of this hyperactivity dramatically decreases. We see this in different animal models. Again, we see it with different kinds of inhibitors, not just this one. So, you know, there's evidence that retinal acid goes up, inhibiting its activity reduces this, inhibiting its receptor reduces the hyperactivity. I'm not gonna show you the evidence that we can mimic hyperactivity in a wild type by injecting retinal acid itself. So that's one way to inhibit the retinal acid receptor is with drugs like BMS 493. I'm calling it a drug, but it really was just a molecule that they made. The reason they were interested in retinal acid receptor inhibitors was as possible cancer chemotherapies. That program was sort of dropped, but there's a lot of, there's a rich pharmacopeia of candidate blockers of RAR. And we'll get back to that a little bit later because we have strong evidence now that we can improve vision dramatically in these mice with this strategy. An alternative strategy instead of blocking the receptor with a small molecule, you can use gene therapy. So it turns out over the years, people studying retinal acid the way it works have come up with a dominant negative version of this retinal acid receptor. So this is a mutant of RAR alpha, which not only doesn't bind to DNA, but it sort of takes down the whole complex so that if you express any of this in a cell, you interrupt the possibility that retinal acid is gonna turn on gene expression. And this can be delivered to neurons by encapsulating the gene in AAV, introducing it into the eye, having it infect retinal ganglion cells. So there are two alternative approaches, either small molecules or gene therapy for blocking the retinal acid pathway. We'll get back to that again at the end. So I've been talking about retinitis pigmentosa as the main sort of application for all of this. What about AMD? So in AMD, there's a much more localized loss of photoreceptors from the macula. And of course, mice and rats do not have a macula. They have a rod dominated retina. And so they don't have any sort of specialized region with all cones. And so you can't really study AMD. In fact, you can't study it in any animal model yet. So the best you can do, I suppose, is just ask what happens if you very locally ablate photoreceptors? In RP, we're talking about mutation that causes the generation of photoreceptors. Here, we're talking about a lesion, if you will, that is caused by implanting some foreign materials subretinally. In this case, it's actually a retinal implant, a subretinal implant. And this doesn't say so here, but this was the result of a collaboration with Daniel Polonker, who's at Stanford. If you implant one of these implants, I'm not showing you this here, but one of the sort of unfortunate consequences of these implants is that they actually destroy the photoreceptors that are remaining in that little region of retina. So we basically have a local ablation of an island of photoreceptors. And what do we see? We see that the retinal ganglion cells overlying that area show enhanced RA-induced gene expression, just like we saw on the RP animals. And they show hyperactive firing. So this is recording from this area where the lesion has occurred and it's not marked here, but from control areas outside with the lesion has occurred and the change, the retinoic acid-induced change is restricted to the area where you've caused this lesion. So it just may be that the same phenomenon applies really to any disorder that causes loss of photoreceptors. The downstream consequence of that may be that retinoic acid is elevated and that there's changes in the operation of the downstream circuitry. So, okay, so let's get back to the question of what all this has to do with vision and how it impacts vision. So to address this question, we use another RP model mouse, but this is one that degenerates slowly. So you can actually catch the degeneration and the remodeling in the act. And you can see physiologically what that looks like in these three recordings. These again are multi-electrode array recordings. This is from a two week old mouse. And what you see here is the response to these periods of light and dark. And you can see that this retin is responding quite normally to illumination. When light turns on, you see this high frequency firing of retinal ganglion cells. And when light turns off, there's a burst of firing from some of the retinal ganglion cells as well. And these presumably reflect activities of on and off retinal ganglion cells. And there's some adaptation that occurs in the continued presence of light. So this, I'm not showing it to you, but if I compare this to a wild type light response, this would look quite normal. Those same mice at one month of age, you can see the story starts changing quite dramatically. The light responses are diminishing greatly. And by the time we get to two months old, the light response is completely gone. So as I said, this is a mouse that has a progressive form of RP. It loses its photoreceptors between two and three months. But if you look carefully, you'll see that the level of background firing is increasing during the same time period. So coincident with the loss of the light response is this sort of game of hyperactivity. And that's shown here. Here's the light response in blue diminishing over time. Oops, sorry. And here is the spontaneous firing of ganglion cells rising over time. And so there's a time period where the retina still has photoreceptors can still generate a light response, but it's already becoming quite hyperactive. And so what if we intervene in retinal gas and signaling right then, you might think that the hyperactivity, if it's obscuring any light responses, maybe the retina would be better at detecting responses to light, maybe the animals sort of behaviorally would have better vision as well. And so we addressed this, we answered this question. We took these RD-10 mice. Here's a mouse, I think this is about 45 days of age or so. When degeneration is progressing, it's lost a lot of its vision. There's a very brief light flash here. You can see in the recording, I can't really make out any particular response to light. That's the eye that was injected with vehicle. And here's the eye that was injected with BMS 493. And you can see that it's a very brief light flash, but there is some spikes that occur right during or after the light flash. And this is the summation of all the spiking in that particular recording. This is if you take nine flashes of light and you average them together from this same recording, you can clearly see that the light response has emerged from the background activity, which by the way is reduced by in the eye that's been injected with BMS 493. And this is now comparison of five different mice, the eye that was injected with drug versus the eye that was injected with vehicle. In every single case, we see quite a significant response to light expressed as firing rate light over firing rate in dark. So we've really sort of pulled this signal out of the noise, if you will. And what this looks like, if you use a variety of light intensities is that particularly at lower light intensities, you dramatically boost the response to light. And these kind of equalize out as you get to more saturating intensities of light. So blocking the retinoc acid, receptor increases, the light response increases sensitivity of light. By the way, it doesn't do anything in a healthy retina. We've done those controls. So that's the electrophysiology of vision. What about vision itself? Do the mice actually see better? And I've already mentioned, how we intervene in this drug pathway at the level of the retinoc acid receptor with BMS 493. So just to run through this again, their vitamin A is converted into retinaldehyde. When photoreceptors die, there's an excess of retinaldehyde which leads to excessive production of retinoc acid. And that turns on gene transcription by binding to the retinoc acid receptor. And that's what causes hyperactivity and hyperpermeability. But in addition to being able to block the retinoc acid receptor, there's another target in this pathway for pharmacological manipulation. And that's the retinaldehyde dehydrogenase itself. And it turns out a drug there as opposed to RAR, there actually is a real drug that is FDA approved, that's been used very commonly for at least 30 years. And it comes from a completely different world than ophthalmology. It's called dysulfurum. It's more common name is ant abuse. And it's used to treat alcoholics who have sort of hopeless addiction to alcohol. And the way this works is when you drink ethanol, ethanol is broken down by, or is converted by alcohol dehydrogenase into acid aldehyde. And then that happens in your liver. And then there's an enzyme or a family of enzymes I already mentioned, aldehydehydrogenases that metabolize the acid aldehyde into acetic acid and water. And disulfurum blocks aldehydehydrogenases. And so if you're on disulfurum, which is taken orally on a daily basis and you drink alcohol, it's converted into acid aldehyde, but then it's stuck at that stage. And that acid aldehyde builds up in your bloodstream and it basically gives you an instant severe hangover. It's called the disulfurum reaction. It's very, it's a, I haven't experienced this personally, but it is very unpleasant. It can even be dangerous. And the idea is that disulfurum then becomes an alcohol deterrent. It was at one point, the first line treatment for severe alcoholism, it's kind of fallen out of favor because maybe punishing people for drinking is not the best approach. So there's other kinds of therapies that have emerged, but it's quite safe when taken for this purpose. And like I said, it's been FDA approved for many, many years. And the prediction is, it turns out that retinaldehydrogenase is one of these aldehydehydrogenases. So if you give people disulfurum, perhaps they'll prevent retinog acid induced remodeling of their retinas and they will see better if they have a degenerative disorder. And so we've tested this in mice using an operant conditioning task where we train mice to recognize a visual stimulus, which is a drifting grating shown on a computer screen. The mice are trained to run on this running wheel and when the image pops up, they learn to associate that image with the availability of some reward that they can get by poking their nose into this little noseboat device. And that delivers a drop of sugar water. We start out with mice that are water deprived. So they're very motivated to get a drop of water and they learn by trial and error to recognize that the image represents the availability of reward. And so we train them over a period of several days by pairing the stimulus, the image, with the reward availability. And with each training session, we decrease the time that the reward is available for. So the mice more and more stringently learn, they've got to go and do that nose poke to get their reward. And after a few days, they've got it. We do all this training when mice are really young. RD10 mice are really young and they still have their normal complement of photoreceptors. And then we put them aside for a month or two while their photoreceptors start to degenerate. And then when that period is done, we can come back and test not only whether they can do this task, but how sensitive they are to changes in the image itself. So here we're changing the contrast of the image and we can measure contrast sensitivity in this manner. So here's an example. Here is the behavior of a single mouse over the course of one testing session. Let's start over here where the stimulus is a full 100% contrast grading.  There's very little variability in the latency of that response. They get it right just about 100% of the time. And as we lower the contrast, you can see that they get worse and worse at getting this correct. And more and more variable. And so this is sort of how we determine contrast sensitivity. We could do this right after training and we could do it a couple of months later when they're starting to lose their vision. And what we see if we do this right after training is that here is the contrast sensitivity curve of the mouse at about five weeks of age. And here it is at about 10 to 12 weeks of age. The gray line here represents the untreated mouse where it's lost a considerable amount of its vision. In fact, it's barely succeeding at all in responding to even 100% contrast image. But if we've been feeding the mice disulfurum during that time, their vision is dramatically retained almost as good as it was if there had been no degeneration at all. And the same is a little less true of BMS 493, but in this case, instead of feeding the mice, the disulfurum were injected in their eye and it's only on board for five days or so before the test. So both of these manipulations really dramatically improve vision. So we've done this at the level of behavior. We've also have collaborators at UC Santa Barbara, Michael Gord, who's a wonderful neuroscientist and friend. And he's looked at the activity of neurons in the visual cortex V1 and using a calcium indicator molecule called G-Camp, which he expresses in these neurons. The idea is that you would express it and the neurons wait a few weeks for the fluorescent indicator to be expressed.  We'll get back to that in a second. And here's what you see in some of these neurons in the cortex. As you change the orientation of the visual image, different neurons tend to light up. These neurons are orientation-tuned. This is what Hubel and Wiesel initially found decades ago in the cat visual cortex. You can see the response of this G-Camp dye in different neurons to different orientations of light. They all have different orientation tuning. And when you lose your photoreceptors, of course, among other things, the cells become worse at discriminating between different orientations. But the whole point is if you've treated these mice with disulfurum or BMS493, the orientation tuning is dramatically improved. This is orientation selectivity index. That's improved both by treatment with disulfurum or BMS493. This is just one of the many things that these guys have evaluated in these cortical neurons. Here's something else that they've evaluated. This is a much more, or the stimulus in this case is much more complex. In fact, instead of being a static image, it's a movie. And the movie happens to be one of the classic film noir movies from the 1950s directed by Orson Welles. It's a movie called Touch of Evil. And this has been used traditionally in neuroscience because it's black and white. And this particular scene I'm about to show you is one continuous scene in the movie which has no cuts and it has a lot of contrast and it's complicated. And I'll just let you watch the movie. It's only a few, it's only about a minute long. Okay, so at the time this was actually pretty technically advanced this particular shot because like I said, it's one piece of camera work and the camera's on a boom that has to go way up in the sky and catch everything at different angles. And I've never, I actually must admit I haven't seen the rest of the movie. And so I don't know whether that bomb in that car blows up or not. And I probably should go and watch it at some point. I'm very curious to know what happens. Anyway, so you wouldn't think that Orson Welles would be so interested in film noir but if you shine that, if you, sorry, play that movie to either one eye or the other of these mice here's, this is the duration of the movie it's about 30 seconds long. And it's hard to see but these are different scenes in the movie. And what you're looking at here is a raster plot of many, many different neurons. I'm sorry, this is three individual neurons but the movie has been shown 30 successive times. And you can see in this neuron there's one scene in the movie where the cell tended to respond. And this neuron it's a different scene in the movie with a different neuron tended to respond. And finally, this third neuron responds at different scenes. And so what it turns out in a healthy mouse with normal vision, a lot of the neurons are tuned to some features of this film of certain scenes. It's hard to know exactly what the features are but the reliability of the response to a particular scene is pretty high. You can see that consistently the cell responds when the movie gets to this particular point in time. This is true of a normal healthy mouse but an already 10 mouse that's losing its photoreceptors it's a whole lot less true. So here's the, I'm not comparing normal to healthy but it goes way down the reliability is greatly reduced. You can see it's only 0.1 or less than 0.1 but disulfurum or BMS dramatically improves the reliability of responding to a particular scene. So this is all evidence that these drugs are actually improving, I realized this was a long roundabout way of saying this but they're really improving vision per se in these mice. And so that's kind of the end of the data of this presentation. But the idea here is that if your retina is losing photoreceptors that's only part of the problem. There is much more going on that involves the rest of the circuitry of the retina. And I didn't go into our more mechanistic studies but we have evidence now that it's not only the ganglion cells becoming hyperactive there's also dramatic changes in bipolar cells in particular their ability to synaptically transmit information to the ganglion cells. And that's also degrading tremendously and that's also rescued by blocking retinoc acid receptors. And so whereas these kind of manipulations are may end up being effective for restoring vision in cases of complete blindness they're not gonna address this other problem which is that the retina itself and maybe even further downstream the way that the system is processing information is getting corrupted. But now we have strategies for correcting that problem. And at least in mice you can correct that problem after the fact. You know, these changes have already occurred and we're blocking either RALDH or RER and we're able to bring that system back almost to where it was before that remodeling had taken place. We haven't looked at the morphological consequences of remodeling actually I'm talking to Brian quite a bit about this and collaborating on this aspect of the project. So and these two approaches I should say are not mutually exclusive. So not only do inhibitors like this not only are they predicted to improve low vision but those same corrupting influences are going to limit how well these vision restoration technologies work. If you regrow photoreceptors from stem cells and the rest of the downstream circuitry is corrupted and not processing information correctly these same inhibitors might correct that problem and sort of potentiate the effect of vision restoration technology. So just in terms of a sort of a verbal summary of this or written summary of this what I've told you today is that photoreceptor degeneration leads to remodeling changes including hyperactivity of retinal gangs themselves and that corrupts neural information processing. This exacerbates that we think a loss of sight and low vision subjects and will undermine new vision restoration efforts in blind subjects. The degeneration of panoramic activity is caused by overly active retinol acid signaling. Pharmacological or genetic inhibitors of either the synthesis of retinol acid or retinol acid signaling can suppress hyperactivity and restore the normal vision information processing capabilities. Dysulfurum which is an LDH inhibitor by inhibiting the retinal form of LDH is a logical first choice for testing in human patients and we are setting up, not really us, it's our colleagues at University of Washington and University of Rochester are setting up a clinical trial with Dysulfurum on RP patients to see if it actually improves their vision. And that may be beginning as early as this fall. The barriers for getting that to happen are low because this is already an FDA approved drug. And once proof of print, and I guess the most important thing about those studies is that if they work, Dysulfurum itself may be a good drug for improving vision but because of all the baggage that comes along with it, I mean, patients would not be able, they'd have to be completely abstinent from drinking alcohol. And we don't really know what the really long-term consequences of blocking all aldehyde clearance would do to a person. It may not be good for as a long-term treatment but once if we can approve proof of principle that it works in humans, retinog acid inhibitor, receptor inhibitors might be more favorable as a long-term treatment. And that includes small molecules, RNA interference drugs that block the expression of retinog acid receptor. These would be RNA therapies like anti-sensal aglomucleotides or small interfering RNAs. And finally, I mentioned AAV for deliver permanently blocking RAR activity with this dominant negative retinog acid receptor. And I should, this is the most important slide, is crediting the people who did, all the wonderful people who did all this work. Most recently, the retinog acid receptor work in my lab was carried out by Michael Tellius who was a post-doc in the lab and he's now on the faculty at University of Rochester Vision Science program I forget the name of their I Institute. Kevin Cow who is a current post-doc in my lab, Bristol Denglinger and other post-doc and various other people. And our collaborators, including Michael Gord at UC Santa Barbara and his graduates in Kevin's City have been just wonderful. And the work we've done together with Daniel Plonker and this work was supported by the National I Institute, Foundation Fighting Blindness, other foundations and several years ago, we started a small commercial enterprise called Photoswitch Therapeutics that is interested in commercializing some of these technologies. So thank you, I'm happy to take questions and discussion items. Thank you very much. Thank you, Dr. Cramer. Well, anyone you can either ask questions via chat or by raising your hands. I'll just start with a question. And these RD-10 mice you're targeting the 10 to 12-week timeframe for the clinical trials with disulfram, how are you determining that intersection of death of photoreceptor versus upper regulation of retinal died? So what level of vision loss are we talking about? Yeah. You know, this is where it gets into sort of clinical evaluation by our colleagues. I mean, clearly these people still have light perception. I think that, you know, the most precise kind of measurements we can do are micro-perimetry where we actually can map the extent of scatomas and really look very fine grained responsiveness to light even down to the level of individual photoreceptors using adaptive optics. So the exact stage and how sort of numbers of all of this, I'd have to ask my colleagues for the numerical, the quantitative numbers about how degraded their vision would need to be. Paul, go ahead. Okay, thank you. That was very interesting. As you may know, for a Stargardt disease, we're looking even earlier in the pathway with RBP-4 inhibitors that would lower vitamin B levels in the eye. Do you think that's doing a similar effect? Have you looked at that? You know, in terms of its effects on retinal acid, hyper-mediated hyperactivity. So I just, I coughed at exactly the instant you said, but could you repeat that once again? Sure, you know, we're looking for RBP-4 inhibitors for Stargardt disease and even for macular degeneration. Do you think that that would affect retinal, have you looked at whether that affects some of the retinoic acid levels and some of the hyperactivity that you're seeing? We have not. Yeah, so I mean, it very well could be working through that mechanism. I mean, there is sort of a conflict here in some ways because for at least certain disorders, vitamin A has supplemented and as a potential treatment. And so I think that's one of the reasons instead of interfering with the metabolism of retinoids we're probably safer downstream. And I mean, what I really favor is this idea of inhibiting the retinoic acid receptor and not messing with retinoid metabolism. So disulfurum is nice because we can do those experiments immediately and we can sort of do trials on humans immediately. But beyond that, I think the advantages are gonna fall on the retinoic acid receptor side of things. All right, thank you. All right, Dr. Kerber, that takes us to the end of our time with you for clinical faculty. Again, on behalf of our faculty, thank you so much for the talk today. Look forward to your other engagements throughout the day. Yes, I will see you in a week or so. Thank you. All right, take care. Thank you.


Welcome to today's presentation entitled Orchid Trusted Parties Functionalities. My name is Jacob White. I'm a Welch Medical Library Informationist, and my pronouns are he, his. Today we are going to cover linking your Orchid ID to trusted parties. One big benefit to having an Orchid ID is the automated record update feature. If you share your Orchid ID with your publisher, the information about your new article will be added to your Orchid when it gets published via the Crossref service. This way you do not have to go into your Orchid account and update every time you have a new publication. If you use your Orchid record to share your publications on a departmental website or a personal website, this new information will automatically appear on those pages as well. This is an example of how a works entry looks when it has been automatically added using Crossref. It will say Source Crossref. Another vendor account you can link your Orchid record to is the Web of Science Researcher ID. If you track your peer review contributions using Researcher ID, you can add that information to your Orchid. This is a step-by-step process for linking your Web of Science and Orchid ID data. You will need to start on the Web of Science homepage, accessed by the Welsh Library website. Start out by creating your Web of Science account and creating your Researcher profile. You have to push the open menu button in the top left corner of the Web of Science homepage in order to access your profile. There are many filters to select from to help filter and locate your data. You can filter by institution, for example, to make it easier to find your articles. If you have already added publications to your Orchid ID, you can skip this part, because syncing between your Web of Science Researcher account and your Orchid ID account goes both directions. Once you have found your publications, you can connect them to your Orchid record as well, using the Orchid syncing tab in your Web of Science profile settings. This step will go most smoothly if you are already logged into your Orchid record in the background, preferably through the Johns Hopkins Orchid registry. If you would like to automatically sync Orchid and Web of Science Researcher ID, turn all of the switches on the Orchid syncing tab to on. This will lead to the Orchid Authorize Access page. And from there, you will give permission to Orchid and Web of Science to read and write into each other's records. Similar to Crossref, when Web of Science identifies a new record affiliated with your Orchid ID, it will add it automatically to your work section in your Web of Science Researcher ID, as well as in your Orchid. Another tool you can use is the Scopus Author ID Scopus Elsevier linker. If your Author ID in Scopus is already set up, it will be very easy to import works. Follow the steps in the Scopus Orchid workflow to find your publications in Scopus and link them to your Orchid. If you have not set up a Scopus Author ID in the past, this step will also help to disambiguate the information in that Author profile as well. When you add a work to your Orchid record using the Scopus Search and Link functionality, it will say added by you via Scopus Elsevier. This brings us to the end of our presentation about trusted parties in Orchid. Thank you very much for your time and attention. Please reach out to us at the email addresses or contact information on this slide if you have any questions.


How do we improve our quality of life? Essentially by doing things differently. How do we do things differently? Essentially by innovation. More and more competitive behavior is focused on innovation. And we see that also with respect to human capital. What we are really trying to do out here is come up with the best understanding that we have today. The most holistic understanding representation of innovation in different economies. And we certainly hope that this model and associated data and framework will enhance understanding of what is happening in the world and help both policymakers and decision leaders in business make the right decisions. We are extremely happy to be in Australia on the 18th of July. We know that the impact will be tremendous on social networks, on all kinds of media. And we invite everybody who cannot join us physically to actually connect, participate, interact because this will be the global launch of 2014.


Here is a list of 10 dictators of Africa, formally saviours of their countries. 10. Charles Taylor. He was the 22nd president of Liberia. 9. Paul Beyer. He has been the president of Cameroon since 1982. 8. Robert Mugabe. Brought freedom to Zimbabweans, only to get himself power drunk. 7. General Sani Abaksha. Ales from Nigeria. And though he only retained power for a five years. 6. Seekhoutour. He declared Guinea a one-party state. 5. Messias Nguema. Nguema was the first president of Guinea. 4. Syed Bah. He ruled Somalia 1969 to 1991. 3. Omar Al-Bashir. Sudanese former military officer. 2. Hisin Herber. His rise to power was from Libya invading Chad. 1. General I.D. Amindad of Uganda


I was here is I like them the way they are I have to be more confident myself.  You literally said you wanted the guys to look at that more No freaking way vlogmas day 11 in effect. How many days away are we guys? We got the big 14 day one four away from Christmas guys Saying I got new glasses, and I'm gonna start being a look like I think I'm gonna start with my glasses more than my contacts I feel like it like comment down below. How do you feel about her glasses? I think she rocks And if you guys see the blue light I got blue light glasses, okay So these are actually my real prescriptions. I had billy bet ice. Yes I got blue lights help protect from our computers or phones because you know, that's our job And she's on her phone all day So she has to get glasses in order to protect your eyes and I'm blind So if I don't have my glasses, I can barely see you guys. Hey, sorry Mariah, but 2020 You know, you know where my 2020 visioners out here is fake my butt But guys if you are finding us through this video Thank you so much for watching make sure to go down and hit that subscribe button because we just hit a million what couple days ago Crazy we literally hit it on Monday, and I am so thankful We are both so thankful for every single one of you guys If you did not go see that video make sure to go check it out You need answers to get some packages. I like I know I know everyone. We're literally always getting packages This is shows Mariah just wants me to leave she wants to kick me out all the time And I can officially film this intro as you guys read by the title today I'm gonna be asking my boyfriend if I can get a boob job and let me just say I do feel very confident in myself to where I Don't feel like I need a boob job because with me honestly I like having smaller boobs just because I don't like to wear a bra I think bras are so uncomfortable and I wish I never had to wear one But it's obviously there's some shirts for I have to wear and also I just want to say if you guys do end up getting a boob job or if you have a boob job Or you want to one day get one. I just want to say I support you guys for me I personally don't want them done But if anybody does do that and it makes them feel more confident and they want to get it done I support you guys and I'm all for people doing things for themselves and making themselves feel pretty in their own skin So I know you know especially during this time of the year It's hard to feel confident in yourself and have that motivation So if that's what's gonna make you motivated, then that's what's gonna make you motivated I support you guys and I love you just for me Obviously, I feel pretty confident with my own boobs So I don't feel like I need a boob job, but that's besides the point today I am so excited to tell Bill that I want a boob job because Bill is gonna be like babe What are you talking about? You look beautiful without it So we're gonna see if he either supports it or if he's gonna be like, no babe That is totally not gonna happen I know Bill supports me no matter what decision that I make but with stuff like this It's obviously a big step and I know he's gonna be trying to help hype me up Hype up my body and tell me how beautiful I am without it Make sure you give this video a big thumbs up if you guys are not always subscribe Hit that subscribe button and join them out with them because team Araya comes back with the most lit pranks It is vlogmas day 11 and I have to stay in the lead by the end of vlogmas I have to be the prank queen. I have to stay up in the lead. You guys already know I come back with the most lit pranks Bill literally thinks he runs a channel or his pranks are so much better And he comes back so good.   Wait, what? What these are the Christmas gifts for you. I was literally just about to say. No, I was literally just about to say I don't understand why I have to go to give Mariah's packages every single time. I'm not gonna lie I did open one of them Luckily this wasn't my stuff. I got leggings, but whatever. We don't care about that guys This girl's always making me go get stuff and What? Hey, why are you looking at your boobs? For your size of a girl, they're perfect. You like them? Yeah, we're still filming baby. I'll talk about your boobs I need to talk to you about something. Oh, I need to go to the bathroom. Can I go to the bathroom first before you talk to me?  I'm gonna talk to you about something. I turned the camera off. It's just there. I just want to talk to you about something I'm gonna ask you something because I know your boobs are not too small. Listen, they're perfect I've been feeling really insecure about my body and I feel like the only way to get myself to feel more confident about myself is To good get a boob job. They just like just like her mom. Stop. Stop.  You really think you're that ugly? No, I don't think I'm ugly. I just feel like do you understand they just don't feel like they look small They are perfect. I know but I have to feel more confident myself and I've been really unmotivated and like I wish I could just plump up. Are you insecure about your body? Because you don't have to be you're beautiful. You're literally like look amazing. Doesn't she look amazing? I don't feel amazing in my own body.  None of your clothes are gonna fit Yes, they will. I mean it's like boobs will look better in that like they'll fit the looks better. I feel like that's up to you Like I know I hate wearing bras and all that stuff but like I'm realizing I don't have to wear breasts It'll already be perky. I don't have to keep anything to lift them up, you know Like they'll just be perky and cute. How long have you been thinking about this? Just like a couple days. I've been just talking to my friends about it. Come here. What did your friends say? They said they said whatever makes you happy like they get it Well obviously whatever Listen listen listen And I just I want boobs like I'm confident in my lips and everything else, but I understand I want my boobs done. Babe, just let me talk. I understand that you want them, but it's up to you ended story It's up to you. So you'll support me if I get them done. Why wouldn't I? It's like look at them. Babe they look perfect to me. Imagine them being like up and they can grab them up. They are. They're perfect. I really don't care. My honest opinion. I like them the way they are. So you would support me if I got them done. Obviously it's not my decision. Come here. You're so sweet. I'm so thankful to have you. It's not my decision. So you love it. Would you like them or would you think they're awkward? Why would you even ask me if I would like them? Yeah, I like anything that you want, but I think they're perfect I don't think you need to do stuff to your body to make your self-esteem feel better though I know but sometimes you know like you wear like I feel like you look better in crew next week. You style your hair a certain way.  The same thing like girls are different like they're boobs and they're butts like they're so those are like two important things that they want to be Someone they want to be proud of and I'm not proud of my boobs. All my boobs be really big and perky. So you want everyone to see them that's why you want to get them done. You want people to be in people's faces. No. You want them to be in people's faces. I never said that. I said I want them to be in people's faces. For you, for you.   Where are you coming up with a bar? You just said that. I did not just say the bar. So you're telling me. What's up and shake them around? That whole sob story was fake. Not a bar. You want to get them done to make people look at you more. Babe, I want to get them done to feel more confident. You're twisting my words. You just said that. You literally said you wanted the guys to look at that more. I did not say that. You said you want people, people, guys and girls, people to notice you more. I did not. I don't want to say that. It's through your movies.  Why don't you just... I'm getting my hair longer, yes. That'll lift yourself to see more. I think you're beautiful. If you want to do it, you do it with your own money. Y'all are too big. You're like 10 grand. 10 grand? To pull up a balloon. It's 10 grand. Feel us not flying. For people that get them done, I think it's totally fine. It's up to them, so it's up to you.  If you want to get them bigger, that's all you. I'm just saying you don't need that because you're beautiful. I was going to ask if you can get a boob job with me. I'll get a boob reducer, but I'll joke aside. You can get it if you want to. Yes, I want to go with you. I want to get big boobies together. No, okay. Let's start filming. Please! No, let's start filming. I'm not getting my freaking boob job. Please. I'll give them a present and you agree that you're not going to boob job with me. Fine. I'll just start filming that. Babe, you... You literally left a recording for four minutes. Hold up. Did you leave a recording on purpose? Are you pranking me? Do you actually want to get a boob job? Wait, tell them I'll be for real. I don't want you to get a boob job with me. I'm like that's serious.  Wait, you're filming a video to see my reaction? Yeah, because I want you to get a boob job with me.  Are you pranking me? Oh my god, guys. I thought you were being dead serious. My heart is racing right now. I was hoping you would say you'd get a boob job with me. Oh my gosh, guys. I wish you could hear it. You couldn't get me boob jobs together. Guys, okay. Did I really just expose myself? Yes, I do get pedicures with Mariah. But that's the farthest I'm going to go. To doing anything like that. And I will never get my nails done with you either. You will never get your nails massaged and stuff. Okay, no. I'm talking about color. You get no chipping, whatever that is. But guys, oh my gosh. No freaking way. Oh, it stopped. If you guys are new to our channel, if you are not, you would already know this. But Mariah literally sneezes every single video. How do you feel? I'm never going to get packages again. This girl is always freaking pranking me when I'm getting packages. No, because I just want a boob job. And I want to see how you'd react. Honestly, no, I'm not serious. But I want to say thank you for being so supportive and being the best boy for never. Why wouldn't I? You are my second half. Guys, I'm hubby material. You're my other half. I love that we support each other. Guys, I'm a freaking amazing boyfriend, guys. I'm a future husband material right here. So of course I'm going to support you. You kidding me? No, in all honesty though, if she did want to get one, it's totally up to her. I don't control her like that. She is her own person. But guys, it is currently Vlogs Day 11. We are on our, what, third day of selling merch? Third day of selling merch, guys. Fourth, by the time you see this video, we have a candy cane collection. If you did not see it. All through December, you guys can purchase this merch. This won't be available after Christmas. It'll be off shelves on January 1st. So December 31st is the last day. New Year's. New Year's is the last day to get it. So make sure to go grab the merch. Link in description. You will freaking love it. And I cannot wait to see everyone wrapping it. We already sold so much. But I know if you wait until like a week before Christmas you probably won't get it. So if you wanted for Christmas, you know, wake up for Christmas wearing your Marvel merch, go for it. If you don't, then either way, you have until the end of December to wear it. Oh yeah, honestly.  So take a screenshot that you bought something and then tag us on Instagram. We will post you on our story and we cannot wait to see in the next month everyone getting their orders and wearing it. So we're going to feed on a Ryan bill. Anyways, how do you feel that I just pranked you? Why are you going to remind me about that? I don't want to think about that. Okay, queen before king. You already know that first of all. Second of all, you do good pranks but I do better pranks. Like that's the thing, I'm just, you know, better. So, look at her. Guys, before you leave, we have to do a $50 giveaway. Because I guess we're ending the video here. Let's see who is going to win the $50 for this video. If you did not know, we give away $50 every single video throughout all of December up until Christmas.  Make sure you subscribe, post notifications on and then comment down why you should be the winner. Like, why do you deserve $50? Some sweet, also like the videos guys. How much do you try to get this video to? Let me like 20,000. You guys have been crushing it recently. We love you guys so much. We're so thankful. $2,000,000. Everyone, if you're watching this and you're not subscribed, help us get to $2,000,000. Let's see how fast we can do it. We did this in two and a half years and that was starting from zero. $2,000,000. I feel like it's going to come way quicker. $2,000,000. Let's get it guys. I wish we could keep these balloons up forever, but you know, they deflate sadly. So the winner of the $50 for today's video is Andrea Media. Shout out to you. Thank you so much for supporting our channel. We love you so much.   We want to know what you guys think we should do. We've literally been thinking about this so much and we want to do something really cool, really sentimental for hitting a million subscribers to get back. And I know last video I said that we were going to figure it out but we're trying to figure out something that's super cool for you guys and we haven't figured it out yet so comment down below. Any ideas, we will be happy to re-respond and heart some of you guys to comments. We'll see you guys in the next video. But until then, peace out you guys.


Ladies and gentlemen, the story you are about to hear is true. Dragnet is brought to you by Chesterfield, made by Liget and Myers, first major tobacco company to give you a complete line of quality cigarettes.  You're assigned to burglary division.  There's no lead to its whereabouts. Your job? Find it. To sell a product, you have to make it good and keep it good. What do the latest reports show about Chesterfield? Well, our research laboratory has compared it with the leading cigarettes in the country. Chesterfield is highest in quality, low in nicotine. Another good reason why thousands of people are changing to Chesterfield every day. Smoke America's most popular two-way cigarette. Regular or king size. You'll find Chesterfield really mild. Really satisfying. Best for you. The documented drama of an actual crime. For the next 30 minutes in cooperation with the Los Angeles Police Department, you will travel step-by-step on the side of the law through an actual case from official police files. From beginning to end, from crime to punishment, Dragnet is the story of your police force in action. It was Wednesday, December 24th. It was cold in Los Angeles. We were working the day watch out a burglary division. My partner's Frank Smith, the boss is Captain Bernard. My name's Friday. I'd gone across the street to buy stamps for some Christmas cards I was sending out. It was 9.15 AM when I got back to room 45. Burglary. I sat out at a table in the squad room and I started to address the cards when Frank walked in carrying a stack of Christmas boxes. Hi, Joe. Hi. Christmas cards, huh? A little late, aren't you? Well, I was going to send them out Monday, but we had that stake out. You ought to get married, Joe. Yeah. It's the only system. Pay does all that stuff for me. Laundry, mail's cards. Only system. Might help. You got a big stack there. I ought to cut down the list. Look at this here. A poultry shop. Yeah. They send me a card every year. I never get anything a poultry. Faye and I ought to go over our list. Cut off a few names. We're brought in here present. Want to open it now? No, I'll wait. I always opened a couple of days before. Why? Well, I'll put you in the spirit ahead of time. I opened Phil's this morning. Who's he? Faye's brother in Denver. Gave me a magazine, one of those funny ones. What do you mean, a comic book? No, one of those funny ones, you know. No, I don't, Frank. Well, some of the pages have holes in them. You look true when there's a picture on the next page. Oh, yeah, I've seen those on the newsstand. They have cloth pasted in. Cloth? In the ad. If you want to buy a suit, they have a sample right there. You mean you can feel it? Reach right out and feel it. There was one for $200. A suit? Sure. Cloth comes from Scotland. What's it made out of? Solid gold? No, they've got a special kind of gold over there. It's real smooth. Not a goat, Frank. A sheep. Well, it's a special kind of sheep, then, because a suit costs $200. You going to get one? I told Faye. She said wear the sample. Anything doing? Fanning and prior, we're in on that market holdup. They come up with anything? Pound of air, nothing else. I hope it stays quiet. I've got more shopping to do. I finished. What'd you get, Ann? Stationary set, some paper and envelopes, leather binding. Joe, you'll never learn. Oh, what's the matter? No woman wants a stationary set. Get her something personal. Well, it's got her initials on it. No, no. You want something more sentimental, romantic. What'd you get, Faye? It's different in her case. What'd you get, Faye? Sewing machine. That's romantic. Well, there's no way. Why didn't you buy her a catcher's mitt? Burgary Friday. Yes, that's right. You have the right department. All right, Father, we'll be right down. No, you can tell us about it there. Goodbye. The old mission church, they've had a theft. Collection money? Statue of the Child Jesus. Frank and I checked out of the office and rode over to the church at the corner of Sunset Boulevard in Maine. The old mission plaza church founded 1781. The year Los Angeles became a Pueblo. The outside was typical early Spanish design, complete with mission arches. It was made of adobe and painted white. They called it the Queen of the Angels. The pod race from down in Mexico building, the devout Mexicans in town still attended services there. 10.05 AM, Frank and I crossed through the courtyard. Used to be the old stable, but the Spanish priest changed all that when it became a mission. Stone masons paved the stable floor and made it a courtyard. They planted grapevines, trees, and flowers. A young priest crossed the courtyard to meet us. He'd been sitting on a stone bench reading his morning prayers as priests had done here for 172 years. We asked for Father Xavier Rojas who communicated with us. We were told he was inside. We entered a side door. The church seemed to glow with hundreds of votive candles flickering on both sides of the altar and at the shrines throughout the church. It was empty except for a few people praying. Surrounding the main altar were several old oil paintings and gold frames. The air was heavy with a scent of advent flowers. We found Father Rojas up near the sanctuary looking at the nativity scene. He told us about the crib. It was a $70 duplication of the scene at Bethlehem. The parishioners had taken up a collection for it 31 years ago. It was put up every year on December 22 and taken down after the holy season. It was beautiful, except that one of the shepherds had lost an arm. The sheep was old and cracked. And the infant Jesus was missing. Father Rojas led us back into the sacristy. I'm sorry to bother you, man. All right, Father. Especially now, the holiday season. We'll cash our checks, Father. Jordan tells what happened. Or what you think happened. I discovered the statue was missing right after the 6 o'clock mass. You saved the six? Yes. I started over to the rectory and stopped by the crib. Was the statue there before mass? I don't know. But it was there last night. How late is the church open? All night. You leave it wide open so any thief can walk in? Particularly thief, Sergeant. You say it was there last night, Father? How late? 10 or 11 o'clock. We had confessions. No one saw it after that? One of the altar boys. He says it may have been there. He thinks it was. Did he see it? He's not sure. What's his name? Pardon me. Here's the schedule. You'll find the names for every mass there. Was there a big crowd at the 6 o'clock mass, Father? Not too many. Seven's the big one. People on their way to work. Did anyone stay after mass, did you notice? Not especially. I came back here, took off the vestments I suppose it was 10 or 15 minutes before I went back in the church. It was empty then? No, people were coming in for the 7 o'clock. Are these the altar boys, James Corneen and Joseph Heffernan? That's right. Joe's the one who mentioned it might have been there. Did you check with the other priest, Father? Before I called you. None of them knows anything about it. Just for a check on the pawn shops, how much the statue worth? In money? Well, that's the point in pawn shops, Father. Only a few dollars. We could get a new one, but it wouldn't be the same. We've had children in the parish. They've grown up and married. It's the only Jesus they know. We understand. And we've had children who died. It was the only Jesus they knew. So many of the people who come here are simple people. They wouldn't understand, Sergeant. It would be like changing the evening star. We'll do our best, Father. That's why it would mean so much to have it back for the first mass on Christmas. It's not very long, Father. Less than 24 hours. If anything turns up here, you know where to get in touch with us. Yes. Sad, isn't it? How's that? In so short a time, men learn to steal. Yes, but consider us, Father. Us? If some of them didn't, you and I'd be out of work. 1050 AM, we notified pawn shop detail. Frank and I checked out the two altar boys. The first one, James Cornyne, said he knew nothing about the missing statue. The second one, Joseph Heffernan, was not at home. His father said he had a part-time job, but he'd haven't gotten in touch with us right after lunch. By 1130 AM, we'd run out of book procedure. We had a man to find. Our only clue, he'd been to church. 1133 AM, we checked the phone books for the names of religious stores in the area. Two of them were closed. We tried the third. When we got there, the only person in the store was an elderly man sitting by a table. In front of him was a large, beautifully carved chest set. We're police officers. My name's Friday. This is my partner, Frank Smith. Great to see you. Caught me in the middle of a big chess match. Where's your partner? Up in San Jose. We've been playing for years. Same match? No, just two or three months on this one. What I meant was we've been playing different matches for years. I see. You know, we do it through the mail. I send him a move. He sends me one. Must keep you on your toes. Except during the holidays, the mail gets all fiddled up. That's no good. Guess not. Slow things down. That's no good. I like to catch him off guard. You, Mr. Flavin? I do know. We never met. Your name's on the window out front. Mr. Flavin, we checked the other two religious stores in this neighborhood. They're closed. It's the best one anyway. 50% European items. We're checking the stores around the Mission Church. For what? Statue of the Child Jesus. Do you have one we could look at? Sure. No, sir, a larger one. You don't want a larger one, unless it's for a church. That's where you want a larger one. Could we see it, please? It's not my duty to butt in. But unless you live in a big place, this will make your living room all a-killer. Yes, sir. Most of the people who go to the Mission Church trade here. Good many of them, especially the kids. Why kids? More religious. Check on yourself. See if kids aren't more religious than you. I'd be so. That's what's wrong with the world. Oh, I don't mean you're wrong with it. Everybody. Yes, sir. What if we get sick to the point, Mr. Flavin? Sure. A lot of people from the Mission Church come in here. Do people ever come in and sell back a religious article? Like a prayer book or rosaries? Yes, sir. Secondhand, you mean? Yes, sir. Now, since I've ever been around, it's silly. Why? People don't have religious articles so they can get rid of them. They have them so they can have them. But if a man had a statue and wanted to sell it, he'd come to a place like this. Sure, but he wouldn't want to sell it. He would if it was stolen. No, sir.  The only place he'd want to go is where crazy people are. You may be right, Mr. Flavin. I don't know what you fellas are looking for, but if it's somebody who stole a statue, he's crazy and you won't find him. You won't find him as long as you live or in a million years. That should cover it. We checked religious stores out as far as Van S. We asked the same questions. The owners gave us the same answers, but none of them were as encouraging as Mr. Flavin. Frank and I had lunch and reported back to the office. It was 1.30 PM when we started into the squad room. The captain was just coming out. I just checked for you in a lunchroom. I know we've been out on that theft of the mission. Make it some action on the Patterson case. They'll locate him? I think he's on the bus from Sacramento. Well, that means the Bakersfield police. We'll wait and see. Oh, one of you fellas, Sergeant Freddie? He is. I'm Joe Heffnen. My father said you wanted to see me. Sit down, son. You didn't have to come in. A phone call would have worked. My father said to get on over. He says that any kid that uses phones is lazy. We want to ask you about this morning. You serve six o'clock mass? Yes, sir. I'm a senior boy, so I get the six.  Yes, sir. That way, if you receive communion, you get to have breakfast sooner. Father Rojas says you think the statue was there before mass. I didn't look, but I have a feeling it was there. A feeling? You know, how you have a feeling about something, but you're not sure. Did you stay around long after mass? I put out the candles and hung up my surplus. How long would that take? About five minutes, maybe. Did any of the people at mass stay on? Some always do, especially ladies. Oh? Maybe they don't finish in time. Where else they start new prayers? I don't know. So when you left, there were still some women there? No, sir. That was at first. After I went back to the sacristy, there was only this one man. What man? He comes at six o'clock all the time. Do you know his name? No, sir. But he works down in Olive, you know, paint shop, where they paint signs. Could you describe him? Sort of medium. He was wearing a suit that didn't match. Didn't match? You know, different pants than coat. How about his age? Always pretty old. Take a guess. About 40, maybe. There's nothing particular about him. Then why do you notice him? I've seen him before. And the bundle, I guess. The bundle? Out in front. I saw him when he was coming out. He had this bundle, and he almost dropped it. How large a bundle? It's hard to say. Come on, son. Was it large or small, the size of the statue? About that big. Yes, sir. We located the sign shop. The suspect didn't work there anymore, but we discovered his name was Claude Stroup. We found out where he lived. 225 p.m., we arrived there. It was a hotel for men, mostly old men, mostly down and outers. It was called the Golden Dream. Police officers, we're looking for Claude Stroup. Hope Claude didn't get in any trouble. So do we, is he in? No. He's got room 307. You can check if you like. He'll take your word. Were you on this morning? Hm? Yeah, the early shift. Well, we don't have shifts. My uncle owns the place. On the shift? Did Stroup spend last night here? Came in about 11. When'd he leave this morning? Around 6, maybe before. He'd come back after? 8 o'clock or so, then left. Supposed to be back at 10. And pulls this trick. What trick? Our program. He knows the other fellas need him. Program? You hear it at the hotel. Every Christmas, we have a program. Put up a tree and sing. They're mostly old fellas. Singing like that makes them remember back when they were kids. Then Jimmy Finn comes on. Jimmy Finn? He shares number 409. His family once had a lot of money, so he tells the fellas about it. Stories about Christmas. How they had this big log in whose grandfather used to start it up. After dinner, everybody turned over his plate, and there underneath was a $20 gold piece. Brand new one. When Stroup came in this morning, did he have a bundle? I didn't see him come in. You said you saw him. I saw him go out after, but not come in. When was that? 8. If you want to look for a bundle, I could give you his key. We don't have a warrant. It's all right. I know about police. It's all right with me. It's not with us. I didn't mean that. I just meant it was all right with me. Good King Wenceslas looked out on the feast of Stephen. They were three old men. We couldn't tell how much better they would have been with Stroup singing the fourth part, but somehow you didn't care. This was Christmas at the Golden Dream, and it sounded fine. Cross was cruel when the poor man came in sight, gathering winter fuel. This is the last rehearsal. They got most of the songs down pat. Sounds pretty good. That's why it's a shame Claude isn't here. He's tenor, and they need him to make it sound just right. Does Stroup have a job? No, sir. He used to have jobs. Not much lately, though. You see where he was going? No, he should have. The fellas need him. Well, he comes there, will you call us? Sure, and not say anything to him. That's right. I hope it's nothing serious for Claude. The fellas' trouble's ought to be over. Troubles? Way back, it wouldn't count. Tell us anyway. Well, I don't know much about it. As much as you know. Now, come on. Well, something back where he used to live, he robbed somebody or something. What else? That's all. It was a long time ago, a way far back. But he forgot it all, the robin and everything. No, not quite. He remembered it this morning. We went back to the office and ran Stroup's name through R and I. If he'd been booked anywhere, we had no record of it, at least not under that name. 4.15 PM, pawnshop detail reported back. No object resembling the statue of the child Jesus had been turned in. 4.18 PM, I hung up the phone. Patterson's on that Sacramento bus. I thought Bakersfield had it. They were supposed to confirm. They did. Properties station. What about Fanning and Pryor? They're still out. Well, they'll be back soon. When's the bus arrive? Six o'clock. There's plenty of time for them to make it. There's more time for you. We're still on that theft. Can't it wait? No. What is it, 10, $15 statue? When's the price determine a case? I realize it's a church statue, but that doesn't give a priority. It's important to them, Captain. Jill and I promised to get it back. What do you got on him? Nothing much. And why are you so big-hearted? Burgary Friday. When? No. Don't say anything. No. Right. It's Claude Stroupe. He just walked into the hotel. He's our suspect. Nobody's late to him? No. You'll keep. You can run him down tomorrow. It'll be too late then. I need it for the first mass in the morning, Skipper. It's kind of a big thing for them. I'm sorry. I can't juggle details around so you can get a statue back. If this time later on, we'll do our best. Yes, sir. You better get over to the station. Yes, sir. Will you call Father Rojas over at the mission? Why? Tell him we're too busy to work on that statue. But we'll do it later. Tomorrow or when we get the chance. Why can't you call him? Well, we better get over to the station. If Patterson's on that bus, we don't want to miss him. All right, I'll call him. Friday? Yeah. I can send Fanning in priority. Might as well stay on that other thing. Whatever you say, Captain. You are listening to Dragnet, the authentic story of your police force in action. There are good reasons why thousands of people are changing to Chesterfield every day. Why Chesterfield is the largest selling two-way cigarette in America. Why Chesterfield is best for me and best for you. People these days want facts. When you want people to use your product, you have to tell them what effect it has on people who do use it regularly. That's why a doctor has examined for almost two years a large group of Chesterfield smokers. 45% of them have, on the average, been smoking Chesterfields for well over 10 years. What is the effect on these people from smoking Chesterfield? No adverse effects. To the nose, throat, and sinuses, says the doctor. Consider Chesterfield's record with these smokers, with millions of other smokers throughout America. Another good reason for you to change to Chesterfield. Regular or king size, Chesterfield is best for me, best for you. 4.43 PM, we arrived at the Golden Dream Hotel. The desk clerk was right. Claude Stroop looked like a man who had his troubles at bargain rates. Your name Claude Stroop? Yes, sir. Police officers, we'd like to talk to you. I didn't do anything against the law. Honest, I didn't do anything against it. You haven't been accused. I want to take you downtown. We'd like to talk to you. No, sir, I'm not going. I'm not going anywhere. I'm not going to talk to anybody. You're half wrong already. 5.15 PM, we returned Stroop for interrogation. He kept his word.  Stroop didn't move for a whole hour. He sat and stared, but he didn't talk. 6.40 PM, we got a final report from pawn shop detail. The shops were closed. There was no statute. Stroop still hadn't talked. Don't you ever want to go home, Stroop? If I was to talk, he wouldn't let me go. Depends on what you'd say. I'd say it wrong, and I wouldn't get home. You won't this way either. I'd like to go, you can bet on that. This is the seventh year we had the program, and I never missed a one, and a single one. Why don't you tell us what happens, Stroop? How would I know you'd let me go? You wouldn't. I might as well, anyway. All right, what happened from Mass on? Well, there was Mass. I came out and started down toward the hotel. Back up. I left my stuff at the hotel, and then I picked up George's car. I didn't steal it. He said I could have it any time I wanted. Only this time I didn't ask him. I took it and started out. Well? I should have asked, but I just didn't. I went over to Grand Avenue for the Christmas bulbs for this fellow's cells in second hand. It was coming out of the lot that I did it. Yeah. The bumper must have caught the other car. Didn't leave too big a dent, but there was this long scratch. I got out and tried to wipe it off with my handkerchief. You know, spit on it like. Only didn't do no good. I didn't think anybody saw. I don't know how you fellas found out about it. I'll check out our records. Right. Stroop, we didn't bring you down here to talk about that. You didn't? No. There's a statue missing from the church, the statue of the child Jesus. You mean I took it? You took a bundle out of church. Yes, sir. That was my other pants for the program tonight. I had a place sewed up, and there was a button on it. You can check. But I wouldn't take a statue. I don't think you would either. He's clear at auto records. Go on home. For the program? You mean it's all right? Good night, Stroop. Good night. Well, we could stay and work on it tonight. Wouldn't do any good. We won't find it. I don't think so. I'll use Kit and the priest to build his hopes up. As we'll go tell him now. 7 27 PM. We found Father Rojas. Frank told him how it was that we couldn't get the statue back by morning, but that we'd keep trying during the week. He said he understood. We told him we had to get on. As Frank and I started to leave, the doors at the main entrance to the church opened. It was a good 200 feet away. It was hard to be sure. But it looked like a small boy drawing a bright red wagon behind him. When he got closer, you could see he was no bigger than a pint of milk. He was a luminous-eyed little Mexican boy with a face as young as yesterday. The priest seemed to know him. Aquito? In the back of the wagon was the missing statue of the child Jesus. He picked it up gently and walked up to the priest. Father Rojas? He just stood there looking up at Father Rojas. It's Paco Mendoza, a boy from Paris. Ask him where he found it. Donde lo encontraste? No le encontré, le cogí esa mañana. He didn't find it. He took it. Why? ¿Por qué? Todos los años Paquito resso por un camioncito rojo. Este año Paquito resso al niño Jesus. Yo prometí al niño Jesus el primero viaje en mi camioncito. This is all through the years he's prayed for a red wagon. This year he prayed to the child Jesus. He promised that if he got the wagon, the child Jesus would have the first ride in it. Prendré el diablo para llevar a Paquito. He wants to know if the devil will come and take him to hell. That's your department, Father. No es el diablo. Esa es ama a Paquito mucho. We crossed over to the sanctuary. With the help of Father Rojas, the young boy replaced the infant Jesus in its rightful place, the crib in the nativity scene. Frank and I could have been wrong, but the small plaster statues seemed to approve. Mary, Joseph, the wise man, Gaspar, Melchior, Baldazar, the old shepherd, the young shepherd, the peasant, they all seemed to approve. Vuelve a tu casa, Paquito. The priest told the boy to go home. He took hold of his wagon, started the long walk out of the church. There wasn't much we could say. There wasn't much to say. We just stood there and watched him go. Halfway up, he turned to look back, and he went on out. I don't understand how he got that wagon today. Don't kids wait for Santa Claus anymore? It isn't from Santa Claus. The fireman fixed old toys and gave them to new children. Paquito's family, they're poor. And locations were changed. Ladies and gentlemen, here is our star, Jack Webb. Thank you, George Phenomenon. Friends, remember your cigarette dealer will be open right up to Christmas Eve, and he can take care of your last minute shopping problems with Chesterfields. Chesterfields and the special Christmas carton featuring the covered bridge. And now, on behalf of the makers of Chesterfield, Ligget and Myers Tobacco Company, there are over 6,000 wholesale distributors and 1,300,000 retail dealers, and of course, all of us on DragNet. We'd like to wish you a very merry Christmas.


Good morning. My name is Dwight Macenville. I'm the director of the Georgetown County Library, and I have a tendency to talk far too long, so I've consolidated my thoughts into a 30-page document, which I'll read to you very slowly. Whenever I as a resident of a small-town area come to an urban place like this one, I always have an agenda. Urban areas always have so many delightful things locked away in their silos. But getting inside them is sometimes difficult, but they always lead to eureka moments. Here in San Francisco, at the California Historical Society on Wednesday, I had one of those eureka moments. After a speeding taxi ride from the airport, followed by a mad dash from the hotel, I barged into the Historical Society's library and I said, San Francisco, here I am. Help me. And the librarians there did. I found in the Helen Hyde papers a clear link between San Francisco, Chicago, and the Charleston Renaissance of the 1920s and 30s, heady stuff to me. But I had to go to that physical location to find that data, and without a subsidy from attending the DPLA as a member of the steering committee, for me that would have been economically impossible. We rural types also have things locked away in our nearly impenetrable vaults that pertain to folks here, for instance, such as letters from a South Carolinian visiting San Francisco a hundred years ago. On April the 17th, 1911, only five years after the great earthquake and the great fire, here's what that visitor said a few excerpts. San Francisco, it is indeed a big bustling, interesting city. There must be many extravagantly rich people here, and many more who are extravagant without the money. Such wonderful shops, and the most exquisite florists everywhere. The city spends more on food and drink than any place I ever saw. About five years ago, the Institute of Museum and Library Services, hello Susan. Sponsored a terrific effort called Connecting to Collections. Connecting to Collections. It educated smaller libraries and museums like mine, especially, about preserving and linking their archives to others. In Georgetown County, South Carolina, where we serve 60,000 people with 30 full-time equivalents at three branches of the Georgetown County Library, we took that message to heart. And here's what we did. Those are hurricanes, and residents here have a special appreciation for buildings, artifacts, photos and memories that have survived. The Georgetown County Library is a part of the preservation through storage and digitization of documents, the creation of oral histories, and the recording of historic places. We've brought all these things together in a vibrant digital library so we can share them with the world. The Georgetown County Digital Library was launched in 2007 and gets an average of two million hits a month. It has over 18,000 images, like 17th century land plots, antebellum newspapers, and of course thousands of historic photos. The history of the nation is shown here in microcosm. Like Georgetown County's gilded plantation era, new technologies of the turn of the century, send these soldiers off to World War I, famous families of the 1920s, the ravages of the Great Depression, World War II operations, and the devastation of Hurricane Udo. We continue to gather collections from rural historic societies and old addicts across the county, adding more pieces to the puzzle of our local past. The Georgetown County Library actively seeks grants that will allow us to preserve the stories of our residents. We have interviewed survivors of the Great Depression, veterans of World War II, folks who weathered local hurricanes, small businesses that have stood the test of time, and local men and women whose personalities and memories are larger than life. We post our videos on our library website, YouTube, and Facebook. DVDs are also available for checkout or can be watched in our state-of-the-art Heritage Center. We also deliver them to local schools when classes are covering these topics. The library has a vibrant creative teen video production program, and our talented youngsters help gather images and information about local historic sites and artifacts. Like Friendfield Slay Village, like the nation's oldest intact sailing vessel, and like a lonely civil war battery, and more. We've produced many documentaries about each site, two of which one honorable mentions from the history channel. These videos can be seen on our library website or checked out for viewing. Each project, each disseminated image, gives the library a chance to not only preserve the past, but also to create a stronger community by sharing processes and products with our local residents. Our efforts have helped bridge the gap between generations, while connecting us with others in America from coast to coast, and with researchers around the world. We've joined with the South Carolina Digital Library, headquartered in Columbia, South Carolina, and I think that the value of the Digital Public Library of America will be to engage archives and other collections across the United States to open and to share their content silos and storage warehouses somehow digitally in the urban, small town, and rural America with great ramifications from coast to coast, and beyond our shores. Rural libraries alone encompass 61% of all library systems in the United States. These small libraries serve 64.7 million people, including 14.4% in poverty. Just think what would happen if in the digital realm, if these rural libraries became fully energized, rural and small town libraries are part of the structural, cultural, dark matter filling the spaces between the bright lights of our urban continental universe. These small libraries increasingly the shimmering spheres in their own communities, and for our nation to pulse fully with the creative power and luminosity, the kinetic charges must flow throughout this entire matrix to bring the possibility of eureka moments to everyone. The Digital Public Library is no less than the catalytic lever that we must engage forcefully soon to empower for everyone here and abroad the bright potential American digital renaissance. Thank you.


The seed was a belief. The belief that a precondition to development, whether human, social or economic, is an education and training system accessible to all. And that was why Commonwealth of Learning was created by Commonwealth heads of government in 1987 to widen access to learning through the effective use of open and distance learning and new communication technologies. Located in Vancouver, Canada, Commonwealth of Learning is the world's only intergovernmental organization solely concerned with promotion, development and sharing of open learning and distance education, knowledge, resources and technologies. Commonwealth governments contribute financially to calls annual budget and three-year plans on a voluntary basis and supply significant in-kind contributions through program partnerships. In addition, Commonwealth of Learning is able to extend its services further through receipt or special grants, fees, partnerships, fundings and contracts. Today, after 15 years, Commonwealth of Learning's achievements have reached all levels and types of learning including basic and non-formal education, agriculture and rural development, health education, technical and vocational training, open schooling, teacher education and tertiary education. Commonwealth of Learning's services and knowledge resources are used by individuals and institutions in all Commonwealth countries and beyond. And more than 40 Commonwealth countries have directly benefited from Commonwealth of Learning's services, expertise and networks. Hundreds of programs, activities and initiatives have been launched by Commonwealth of Learning over the last 15 years. All of these emerged out of its role as a catalyst for collaborative action, marshalling the available wealth of experience, talent and resources for the benefit of the Commonwealth by developing partnerships and alliances with international, intergovernmental and non-governmental agencies and local and regional institutions in the promotion and application of open and distance learning. Southern African countries is a case in point. Recognizing that innovative training methods are necessary to bridge this gap and that participating countries can ill afford to remove untrained teachers from classrooms, educators from eight Southern African countries, Botswana, Malawi, Mozambique, Namibia, South Africa, Tanzania, Zambia and Zimbabwe collaborated with the Commonwealth of Learning to develop distance education training materials aimed at upgrading teachers working in the areas of upper primary and junior secondary, science, technology, mathematics and general education called Stamp 2000+. In the area of upgrading of professional qualifications, the Commonwealth of Learning's work in the Caribbean on behalf of the Government of Canada is yet another pointer to what collaborative action can achieve. Similarly in South Asia where over 1500 students in Bangladesh, India, Pakistan and Sri Lanka have enrolled in the jointly developed Commonwealth Master of Business Administration and Master of Public Administration program. Eight courses have been acquired and adapted while four more have been prepared and another ten are being developed. Spurred by the success of this program, a number of African universities have expressed interest in establishing a consortium to deliver the Commonwealth Master of Business Administration and Master of Public Administration program throughout the sub-Saharan Africa. Commonwealth of Learning has also responded to a request by Commonwealth Ministers of Education to explore the creation of a virtual university to support higher education in small states. Its recommendations were endorsed by Commonwealth Ministers of Education and Heads of Government in late 2003. Food security, environmental sustainability and poverty reduction too are on the agenda of Commonwealth of Learning. Commonwealth of Learning has also successfully developed collaborative programs with several national agricultural research, education and training institutions in India and in Africa that build capacity for the use of technology in open and distance learning for agricultural and rural development. During its last three-year plan, 2000 to 2003, Commonwealth of Learning lived up to its reputation as a leader in the field of training for open and distance education professionals. From the development of policies and methodology to the actual practice of open, distance and technology-mediated learning. The Rajiv Gandhi Fellowship Scheme, first piloted in 1995 with students from 15 countries, is a two-year distance-delivered Masters of Distance Education program for education administrators. It is developed in collaboration with the Indira Gandhi National Open University in India. Again in India, the Commonwealth Educational Media Center for Asia, SEMCA, is engaged in promoting the meaningful, relevant and appropriate use of information and communication technologies to serve the educational and training needs of the Commonwealth Member States of Asia, in Bangladesh, Brunei, India, Malaysia, Maldives, Pakistan, Singapore and Sri Lanka.