Podcasts about Homology

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Best podcasts about Homology

Latest podcast episodes about Homology

Rare Disease Discussions
Transforming Clinical Outcomes With Early Treatment of Lysosomal Disorders

Rare Disease Discussions

Play Episode Listen Later Apr 4, 2025 60:10


This CME program provides information on best practices to manage children with lysosomal disorders who have been identified by newborn screening. WIth the wide range of symptoms and severities that present for these rare conditions, it is not always certain when the best time to start treatment is in these patients.Continuing Education InformationThis continuing education activity is provided by AffinityCE and the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC). This activity provides continuing education credit for physicians. A statement of participation is available to other attendees.To obtain credit, visit https://checkrare.com/learning/p-transforming-clinical-outcomes-with-early-treatment-of-lysosomal-disorders/ Faculty and DisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Ozlem Goker-Alpan MDFounder and CMO, Lysosomal & Rare Disorders Research & Treatment CentersDr. Goker-Alpan is on the Advisory Board/Consultant for Chiesi, Takeda, Sanofi, Prevail/Lilly, Sparks Therapeutics, Uniqure, Exegenesis, Astellas, Freeline, Team Sanfilippo. She receives grants/research support from Chiesi, Sanofi, Takeda, Prevail/Lilly, Spark Therapeutics, Amicus, Freeline, Sangamo, Cyclo, Odorsia, DMT, Homology, Protaliz. She is on the speaker bureau for Sanofi, Takeda, Amicus, ChiesiDavid F. Kronn MDAssociate Professor of Pathology and Pediatrics                                                New York Medical CollegeDr. Kronn is on the Advisory Board for Sanofi. He is also on the speaker bureau for Sanofi. He receives research funding from Sanofi.Uma Ramaswami FRCPCH, MDRoyal Free London Hospitals & Genetics and Genomic Medicine, University College LondonDr. Ramaswami is on the Advisory Board for Amicus, Chiesi, Sanofi and Takeda. She receives research grants from Chiesi and Intabio.Liz Jalazo MDAssistant Professor of Pediatrics and GeneticsUniversity of North Carolina at Chapel HillDr. Jalazo is on the Advisory Board for Sanofi and Ionis. Lindsay Torrice MSN, CPNP-PC MDAssistant Professor of PediatricsUniversity of North Carolina at Chapel HillMs. Torrice has no financial relationships to disclose.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME's Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible companies. All relevant financial relationships for faculty were mitigated by the peer review of content by non-conflicted reviewers before the commencement of the activity.Learning ObjectivesAt the end of this activity, participants should be able to:•     Cite the importance of early diagnosis and treatment of lysosomal storage disorders•     List the guidelines for the early treatment of LDs and enhanced integration of newborn screening programs•     Identify key research gaps and priorities and strengthen collaboration among researchers and healthcare professionals•     List the educational resources and support programs for familiesPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other healthcare professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity.Commercial SupportThis activity was supported by educational grants from Takeda, Sanofi, and Chiesi.Participation CostsThere is no cost to participate in this activity. CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.com.Send customer support requests to cds_support+ldrtc@affinityced.com.

Ken Ham on SermonAudio
Is Homology Evidence for Evolution?

Ken Ham on SermonAudio

Play Episode Listen Later Jan 11, 2025 1:00


A new MP3 sermon from Answers in Genesis Ministries is now available on SermonAudio with the following details: Title: Is Homology Evidence for Evolution? Subtitle: Answers with Ken Ham Speaker: Ken Ham Broadcaster: Answers in Genesis Ministries Event: Radio Broadcast Date: 1/10/2025 Length: 1 min.

Ken Ham on SermonAudio
Is Homology Evidence for Evolution?

Ken Ham on SermonAudio

Play Episode Listen Later Jan 11, 2025 1:00


A new MP3 sermon from Answers in Genesis Ministries is now available on SermonAudio with the following details: Title: Is Homology Evidence for Evolution? Subtitle: Answers with Ken Ham Speaker: Ken Ham Broadcaster: Answers in Genesis Ministries Event: Radio Broadcast Date: 1/10/2025 Length: 1 min.

Answers with Ken Ham
Is Homology Evidence for Evolution?

Answers with Ken Ham

Play Episode Listen Later Jan 10, 2025


The many similarities we observe among living things is called “homology.” It's often used as evidence of descent from a common ancestor.

Ageless and Outrageous
Clitoral Chronicles: The Science of Satisfaction

Ageless and Outrageous

Play Episode Listen Later Jun 12, 2024 18:07


Many women struggle to have solely have orgasms through vaginal penetration, and today's podcast episode dives into the reasons behind it. Through an understanding of female anatomy, it becomes clear that direct clitoral stimulation is often essential for orgasm. The podcast also discusses how the position of the clitoris relative to the vaginal opening affects a woman's likelihood of experiencing orgasm during penetration. Supporting data is presented, highlighting the significance of clitoral stimulation. Techniques such as double stimulation, using specific vibrators, and improving anterior vaginal wall stimulation are explored as well as ways to increase the chances of orgasm with penetration. The concept of the G-spot is examined, with emphasis on the need for more research. Lifting the pelvic floor and utilizing its strength during penetration is also discussed as a technique for enhancing stimulation. The episode concludes by suggesting that the best approach may involve combining multiple techniques to find what works best for each individual. Key moments in this episode are: 01:01 Homology in male and female structures 02:30 Need for direct clitoral stimulation 03:39 Research on distance between clitoris and vaginal opening 04:42 Why women have differing distances between clitoris and vaginal opening 05:52 Our debt to Marie Bonaparte 07:05 First technique--double stimulation 09:02 Intro to the G spot 09:35 History of Dr Graffenberg 11:27 Research to identify the G spot subjectively 12:27 Research to identify the G spot with ultrasound 13:33 Second technique--improve G spot stimulation 14:42 Third technique--lift the pelvic floor Learn more about lifting the pelvic floor here: https://www.foundationsfl.com/btl-emsella Follow us! Instagram @foundationskristinjacksonmd Website https://www.foundationsfl.com/ FB facebook.com/advancedurogynecology Loved this episode? Share with a friend.

Anchored by Truth from Crystal Sea Books - a 30 minute show exploring the grand Biblical saga of creation, fall, and redempti

Episode 265 – The Truth in Genesis Welcome to Anchored by Truth brought to you by Crystal Sea Books. In John 14:6, Jesus said, “I am the way, the truth, and the life.” The goal of Anchored by Truth is to encourage everyone to grow in the Christian faith by anchoring themselves to the secure truth found in the inspired, inerrant, and infallible word of God. Script: (Bible quotes from the New Living Translation) Then the LORD said to Job, “Do you still want to argue with the Almighty? You are God’s critic, but do you have the answers?” … Then the LORD answered Job from the whirlwind: “Brace yourself like a man, because I have some questions for you, and you must answer them! Job, Chapter 40, verses 1 and 2 and verses 6 and 7, New Living Translation I am the Alpha and the Omega—the beginning and the end,”says the Lord God. “I am the one who is, who always was, and who is still to come—the Almighty One”… Don’t be afraid! I am the First and the Last. I am the living one. I died, but look—I am alive forever and ever! And I hold the keys of death and the grave.” Revelation, Chapter 1, verse 8 and verses 17 and 18, New Living Translation ******** VK: Hi! I’m Victoria K. Welcome to Anchored by Truth brought to you by Crystal Sea Books. I’m here today with RD Fierro, author, founder of Crystal Sea Books, and part-time mechanical engineer. He changes the air filter in the air conditioner. And speaking of changing things, today we are closing out the series that we’ve been presenting for several episodes that we’ve been calling The Truth in Genesis? So today we’re going to be doing a bit of a recap of all the subjects that we’ve covered and hit the highlights of some of the major things that we’ve learned. RD, would you like to say a brief word of introduction about today’s show? RD: I would. Our “The Truth in Genesis” series was designed to allow listeners to hear a sample of the scientific evidence that is relevant to two of the most important topics that affect Biblical inspiration and infallibility: the age of the earth and universe and the origin and diversity of life. One of the biggest challenges facing most Christians is right at the beginning of the Bible in Chapter 1 where the Bible tells us that God created the heavens, the earth, and everything that exists on the earth including all living creatures and most especially, us. Supposedly, that claim is at odds with what contemporary science tells us about the universe and life. So, for a Christian to maintain their faith in the Bible today culture they must immediately confront the cultural challenge to the Bible’s proclamation about creation. In effect, our culture demands that we either surrender our faith in the Bible or our acceptance of science as a source of truth. I believe that we’ve shown through the episodes in this series that conscientious Christians don’t need to make that kind of a false choice. VK: Your contention is that we have illustrated through the episodes in The Truth in Genesis series there is substantial scientific evidence that absolutely supports, the belief that the plain language of Genesis may be accepted as literal, historical fact. And today we want to review and summarize just a few snippets of what we’ve learned. But before we get too far into our discussion about the serious stuff, we’d like to start by just listening to a poetic summary of the state of this debate. To do that we want to play a portion of Crystal Seas’ upcoming poetic series called the Genesis Saga. For today, let’s listen to Part 5 of the Genesis Saga which – aptly enough - we call The Truth in Genesis. ---- TRUTH IN GENESIS VK: That is a pretty amazing summary - and it rhymes. So let’s go back and cover briefly some of the main points of evidence that we’ve learned about from Truth in Genesis that support the fact that the universe and earth aren’t nearly as old as is commonly believed. Let’s also talk about how it would be impossible for the random, chaotic action of inanimate atoms and molecules to spontaneously give rise to life. RD: Well, to start let’s be clear about the competing truth claims that we are examining. The Bible clearly claims that God created the heavens and earth and all the life that exists on the earth, whether plant or animal. And, according to most traditional interpretations, God performed His creative activity on the order of several thousands of years ago. Also, when it comes to animal life the Bible created all the “kinds” of animals that exist today. Contrary to the strawman version of Biblical creation that critics like to shoot at, “kinds” does not refer to the species that are extant today. Nor does the Biblical term “kind” refer to any particular taxonomic level such as an order or genus. It primarily refers to the ability of any two animals to reproduce regardless of how those animals might be classified according to current taxonomy. By contrast the dominant view among most scientists today is that the universe is 14 billion, or so, years old and that the earth is 4.5 billion years old. Also, most conventional biologists believe that life on earth evolved from primitive forms to more complex forms, likely starting with some sort of a self-replicating molecule that over time spontaneously aggregated into a single cell, and that from that cell all the amazing biodiversity we see around the globe today emerged – without direction or instruction from any intelligent source. As our guest for most of our shows, Dr. Jonathan Sarfati, puts it – a “goo to you” form of evolution. VK: Those are two very clearly contrasting views. But isn’t there sort of a middle ground that some have termed “theistic evolution?” This is the view that God created everything but then used evolution as a sort of intermediate mechanism to allow life to progress from simple forms to more complex ones and that over time many different forms of plants and animals emerged from the process that God originated. RD: You are absolutely correct that there have been various attempts to bridge the gaps between Biblical creationism and a materialist, secularist form of evolution. The problem is that most of these “middle ground” approaches suffer from the same faults as the ones that afflict a purely materialistic evolution plus they create additional theological or Christological problems for Christians who hold them. For instance, any approach that presumes that God used evolution to produce man from some lower form of pre-human hominid requires that death preceded Adam and Eve’s fall – and that’s if they accept the fall as being a historical event. Yet various scriptures, such as Romans 5:17, tie death directly to Adam’s sin. Further, if Adam’s fall wasn’t a literal event that introduced death into a creation that God had deemed “very good,” then why was it necessary for Christ to die on the cross to undo the effects of sin. VK: So, you’re saying the middle ground approaches really don’t bridge the gap and allow both sides to be right. But are you also saying that the middle grounds are subject to the same criticisms scientifically as a purely secularistic evolutionism. RD: Yes. For instance, one of the problems we learned about insofar as evolution is concerned is the absence of transitional forms in the fossil record, a fact that even Charles Darwin noted and lamented. When you study the fossil record species appear suddenly and fully formed with very few specimens that can even be offered up as being transitional. Despite the fact over 90% of the fossils that have been discovered were discovered after Darwin wrote the Origin of Species there aren’t any more convincing transitional examples known to today than when Darwin lamented their absence. This absence of transitional fossils would be a problem for any form of evolutionary hypothesis whether theistic or not. VK: What are a couple of other examples of problems that cast doubt on evolution regardless of which form is being discussed? RD: Well, there’s what’s been called by one writer “the failure of homology.” Homology is the idea that certain structures present in different species have a structural or other biological resemblance to each other. The classic example is the pattern in the bones of vertebrate limbs. In a wide variety of mammal species, example, from bats to whales to horses to people, there’s a consistent pattern of having one bone in the upper part of the limb (our arms or legs), connected to two bones, that are then connected to a series of five bones that have 2 segments in the large bone (thumb, big toe) and 3 segments in the other four. Such so-called “homologous” structures are thought to be evidence of “common descent.” In other words some ancient ancestor of all mammals had this pattern of bones so all the mammals in the world today that are descended from the ancestor inherited this pattern. VK: Certainly, at least on the surface, that makes sense. So what’s the problem? RD: The problem is that when Darwin wrote about the support that homology provided for his theory science knew very little about embryology – the study of how life develops following conception. Today, we know a lot more and we now know that the seeming homologous structures in adult animals don’t arise from similar embryological processes or from identical or similar genes. In other words while the adult features seem to be similar they come about from significantly varying developmental processes. This directly conflicts with the notion that the supposedly homologous structures came from a common ancestor because if all the common features were inherited from a common ancestor that ancestor would have passed along its embryological features not just the adult result. There’s a good discussion of this problem in Michael Denton’s book entitled Evolution: A Theory in Crisis. Chapter 7 for those who want to study further. VK: So just like with the fossil record, evidence that is often used to demonstrate the truth of evolution actually has significant scientific problems. Are there any other illustrations of scientific problems with the “particles to people” view of evolution? RD: There are actually lots of them and Dr. Sarfati discussed a number of them during his time in the Anchored by Truth studio. VK: For instance? RD: For instance, just about every proposed mechanism for how life could have arisen from non-living chemicals involves some variation on Darwin’s musings about a “warm little pond” – in other words the notion that the primordial oceans contained a nutrient rich broth that is sometimes termed “pre-biotic soup.” The chemicals necessary for life were supposed to have been present in this soup in such densities that random collision between the right molecules produced abiotic organic compounds that were then used to assemble the first cell or at least the cell’s precursor, whatever that would have been. The existence of these abiotically produced organic compounds is absolutely essential for the scheme to have worked. The problem is that rocks of purportedly great antiquity, by conventional dating, methods have extensively examined and none contain any evidence of these abiotically produced organic compound even the so-called “dawn rocks” of Western Greenland that were supposedly laid down within 3 or 4 hundred million years of the earth’s formation. The same thing is true of all the other rocks of similar antiquity. VK: So the rocks contain no evidence of this pre-biotic soup and without it the whole origin hypothesis falls apart. But some scientists now believe that the earliest life was formed underwater near these heating vents in the deep ocean. RD: Yes. That hypothesis is frequently mentioned in ocean exploration programs on one or another science channel. The problem with this theory is that all life depends on very lengthy chains of amino acids that are called polypeptides. Well, polypeptides won’t form in the presence of excess water. Even if the requisite amino acids were present they wouldn’t combine into the lengthy polypeptides so again there’s an absolute chemical barrier to life starting underwater hypothesis. VK: In other words the difficulties against life having arisen spontaneously from non-living chemicals are starting to stack up like a bricks in a brick wall. Are there any other bricks that are problematic? How about the famous experiments by Stanley Miller and Harold Urey? Didn’t they create the chemicals needed by life when they stimulated a chemical medium with methane, ammonia, hydrogen, and water using electric discharges? RD: Urey and Miller were successful at creating organic compounds. That much is true. But the good news pretty much ends there. VK: How so? RD: First, there is no evidence that the conditions Urey and Miller used in their lab were present in the primordial earth. At a minimum, they used an oxygen free atmosphere because oxidation would quickly break down any organic chemicals that formed. Think rust. But there is evidence of oxidation in supposedly ancient rocks so it’s more likely that the early atmosphere contained oxygen than that it didn’t. Next, amino acids come in two varieties: levorotary and dextrorotary. The amino acids that support life are all levorotary. Dextrorotary forms are lethal. The combination of the two is called a racemate. Miller’s experiments and others since only produce racemates, never pure levorotary amino acids. Third, the amino acids they produced were captured in special traps. If those traps hadn’t been there the amino acids would have broken down before they could be determined to be present. Moreover, Urey and Miller’s experiment where they produced the amino acids wasn’t the first experiment they conducted. They had done others where they didn’t get anything. So, even when they got a result it involved the application of a considerable amount of intelligence. It was the exact opposite of the operation of blind chance. VK: Wow. That last thought really forces you to think doesn’t it? Even if a team of scientists today were successful at producing life in a test tube or laboratory beaker that wouldn’t demonstrate that life could have formed randomly or chaotically. Because - presumably - the scientists would have been applying intelligent guidance and decision making at every step within their process. And, of course, that’s assuming they had duplicated exactly the conditions on the earth at the time life is supposed to have formed and that is, and always will remain, unknowable. Well, this truly has been a remarkable series and yet we really have only skimmed the surface of all these topics. But the takeaway for the series and as well as from each episode is that faithful, committed Christians can believe in the truth of Genesis without having to give up their confidence in real science. As you would expect of an almighty and all-knowing Creator, He has provided His special revelation in a way that is entirely consistent with the way that He created and sustains the universe. Sounds like a great time to praise our Creator in prayer. ---- PRAYER OF ADORATION FOR THE CREATOR (radio version) VK: We’d like to remind our audience that a lot of our radio episodes are linked together in series of topics so if they missed any episodes or if they just want to hear one again, all of these episodes are available on your favorite podcast app. To find them just search on “Anchored by Truth by Crystal Sea Books.” If you’d like to hear more, try out crystalseabooks.com where “We’re not famous but our Boss is!” (Bible Quotes from the New Living Translation) The Book of Job, chapter 38, verses 4 through 7 The epistle to the Colossians, chapter 15 verses 1 through 17 https://creation.com/right-perspective-interpreting-data

Ground Truths
Michelle Monje: The Brain in Long Covid and Cancer

Ground Truths

Play Episode Listen Later Feb 25, 2024 43:57


Transcript with audio and relevant external links, recorded on 6 Feb 2024Eric Topol (00:05):Hello, this is Eric Topol with Ground Truths, and I have a remarkable guest with me today, Professor Michelle Monje, who is from Stanford, a physician-scientist there and is really a leader in neuro-oncology, the big field of cancer neuroscience, neuroinflammation, and she has just been rocking it recently with major papers on these fields, no less her work that's been on a particular cancer, brain cancer in kids that we'll talk about. I just want to give you a bit of background about Michelle. She is a National Academy of Medicine member, no less actually a National Academy of Medicine awardee with the French Academy for the Richard Lounsbery Award, which is incredibly prestigious. She received a Genius grant from the MacArthur Foundation and is a Howard Hughes Medical Institute (HHMI) scholar, so she is just an amazing person who I'm meeting for the first time. Michelle, welcome.Michelle Monje (01:16):Thank you. So nice to join you.Long Covid and the BrainEric Topol (01:18):Well, I just am blown away by the work that you and your colleagues have been doing and it transcends many different areas that are of utmost importance. Maybe we can start with Long Covid because that's obviously such a big area. Not only have you done work on that, but you published an amazing review with Akiko Iwasaki, a friend of mine, that really went through all the features of Long Covid. Can you summarize your thoughts about that?Michelle Monje (01:49):Yeah, and specifically we focused on the neurobiology of Long Covid focusing on the really common syndrome of cognitive impairment so-called brain fog after Covid even after relatively mild Covid. There has been this, I think really important and exciting, really explosion of work in the last few years internationally trying to understand this in ways that I am hopeful will be beneficial to many other diseases of cognition that occur in the context of other kinds of infections and other kinds of immune challenges. But what is emerging from our work and from others is that inflammation, even if it doesn't directly initially involve the nervous system, can very profoundly affect the nervous system and the mechanisms by which that can happen are diverse. One common mechanism appears to be immune challenge induced reactivity of an innate immune cell in the nervous system called microglia. These microglia, they populate the nervous system very early in embryonic development.(02:58):And their job is to protect the nervous system from infection, but also to respond to other kinds of toxic and infectious and immune challenges. They also play in healthy conditions, really important roles in neurodevelopment and in neuroplasticity and so they're multifaceted cells and this is some population of those cells, particularly in the white matter in the axon tracks that are exquisitely sensitive it seems to various kinds of immune challenges. So even if there's not a direct nervous system insult, they can react and when they react, they stop doing their normal helpful jobs and can dysregulate really important interactions between other kinds of cells in the brain like neurons and support cells for those neurons like oligodendrocytes and astrocytes. One common emerging principle is that microglial reactivity triggered by even relatively mild Covid occurring in the respiratory system, not directly infecting the brain or other kinds of immune challenges can trigger this reactivity of microglia and consequently dysregulate the normal interactions between cells and the brain.(04:13):So important for well-tuned and optimal nervous system function. The end product of that is dysfunction and cognition and kind of a brain fog impairment, attention, memory, ability to multitask, impaired speed of information processing, but there are other ways that Covid can influence the nervous system. Of course there can be direct infection. We don't think that that happens in every case. It may not happen even commonly, but it certainly can happen. There is a clear dysregulation of the vasculature, the immune response, and the reaction to the spike protein of Covid in particular can have very important effects on the vessels in the nervous system and that can trigger a cascade of effects that can cause nervous system dysregulation and may feed directly into that reactivity of the microglia. There also can be reactivation of other infections previous, for example, herpes virus infections. EBV for example, can be reactivated and trigger a new immune challenge in the context of the immune dysregulation that Covid can induce.(05:21):There also can be autoimmunity. There are many, we're learning all the different ways Covid can affect the nervous system, but autoimmunity, there can be mimicry of some of the antigens that Covid presents and unfortunate autoimmunity against nervous system targets. Then finally in severe Covid where there is cardiopulmonary compromise, where there is hypoxia and multi-organ damage, there can be multifaceted effects on the nervous system in severe disease. So many different ways, and probably that is not a comprehensive list. It is certainly not a mutually exclusive list. Many of these interactions can happen at the same time in the same individual and in different combinations but we're beginning to wrap our arms around all the different ways that Covid can influence the nervous system and cause this fairly consistent syndrome of impaired attention, memory, multitasking, and executive functions.Homology with Chemo BrainEric Topol (06:23):Yeah, well there's a lot there that you just summarized and particularly you highlighted the type of glia, the microglia that appear to be potentially central at least a part of the story. You also made analogy to what you've seen with chemotherapy, chemo brain. Maybe you could elaborate on that.Michelle Monje (06:42):Yeah, absolutely. So I've been studying the cognitive impairment that can happen after cancer therapies including chemotherapy, but also radiation and immunotherapy. Each time we develop a new model and dig in to understand what's going on and how these cancer therapies influence the nervous system, microglia emerge as sort of the unifying principle, microglial reactivity, and the consequences of that reactivity on other cell types within the nervous system. And so, understanding that microglia and their reactive state to toxic or immune challenges was central to chemotherapy induced cognitive impairment, at least in preclinical models in the laboratory and confirm by human tissue studies. I worried at the very beginning of the pandemic that we might begin to see something that looks a lot like chemotherapy induced cognitive impairment, this syndrome that is characterized by impaired attention, memory, executive function, speed of information processing and multitasking. When just a few months into the pandemic, people began to flood neurologists' office complaining of exactly this syndrome. I felt that we needed to study it and so that was the beginning of what has become a really wonderful collaboration with Akiko Iwasaki. I reached out to her, kind of cold called her in the midst of the deep Covid shutdown and in 2020 and said, hey, I have this idea, would you like to work with me? She's as you know, just a thought leader in Covid biology and she's been an incredibly wonderful and valuable collaborator along the way in this.Eric Topol (08:19):Well, the two of you pairing up is kind of, wow, that's a powerful combination, no question. Now, I guess the other thing I wanted to get at is there've been many other studies that have been looking at Long Covid, how it affects the brain. The one that's frequently cited of course is the UK Biobank where they had CT or MRI scans before in people fortunately, and then once they had Covid or didn't get Covid and it had a lot of worrisome findings including atrophy and then there are others that in terms of this niche of where immune cells can be in the meninges, in the bone marrow or the skull of the brain. Could you comment on both those issues because they've been kind of coming back to haunt us in terms of the more serious potential effects of Covid on the brain?Michelle Monje (09:20):Yeah, absolutely and I will say that I think all of the studies are actually quite parsimonious. They all really kind of point towards the same biology, examining it at different levels. And so that UK Biobank study was so powerful because in what other context would someone have MRI scans across the population and cognitive testing prior to the Covid pandemic and then have paired same individual tests after a range of severity of Covid infection so it was just an incredibly important data set with control individuals in the same cohort of people. This longitudinal study has continued to inform us in such important ways and that study found that there were multiple findings. One is that there appears to be a small but significant atrophy in the neocortex. Two that there are also abnormalities in major white matter tracts, and three, that there is particular pathology within the olfactory system.(10:30):And we know that Covid induces as a very common early symptom, this loss of smell. Then together with those structural findings on MRI scans that individuals even with relatively mild acute disease, exhibited long-term deficits in cognitive function. That fits with some beautiful epidemiological studies that have been done across many thousands of individuals in multiple different geographic populations. Underscoring this consistent finding that Covid can induce lasting cognitive changes and as we begin to understand that biology, it fits with those structural changes that are observed. We do know that the olfactory system is particularly affected and so it makes sense that the olfactory system, which show those structural changes, the neocortical and white matter changes evident on MRI fit with what we found microscopically at the cellular and molecular level that highlighted a loss of myelinating oligodendrocytes, a loss of myelinated axons, a deficit in hippocampal new neuron production. All of those findings fit together with the structural changes that the UK Biobank study highlighted. So clearly this is a disease that has lasting impacts, and the challenge is to understand those better so that we can develop effective interventions for the many, many millions of people who are still struggling with decreases in their cognitive function long after Covid exposure affecting the world population.The Brain's Immune SystemEric Topol (12:17):Yeah, that's a great summary of how the Biobank data UK aligned with the work that you've done and I guess the other question just to round this out is for years we didn't think the brain had an immune response system, right? Then there's been a wakeup call about that, and maybe you could summarize what we know there.Michelle Monje (12:41):Absolutely. Yes, the brain is not, we used to call the nervous system an immuno privilege site, and it is not hidden from the immune system. It has its own and distinct immune system properties, but it's very clear from work by Jony Kipnis and others that there are in fact lymphatics in the nervous system. These are in the meninges. It's also become increasingly clear that there is a unique bone marrow niche in the skull from which many of the lymphocytes and other kinds of immune cells that survey and surveil the brain and spinal cord, that's where they come from. That's where they develop and that's where they return and the lymphatic drainage of the nervous system goes to distinct places like the posterior cervical lymph nodes. We are now understanding the sort of trafficking in and out of the nervous system of cells, and certainly understanding how that changes in the context of Covid, how those cells may be particularly responsive to the immune challenge initiated in the respiratory system is something that is an area of deep importance and active exploration. In fact, some of my ongoing collaborations and ongoing lab work focuses on exactly this question, how does the trafficking from the brain borders into the nervous system change after Covid? And how does potentially cellular surveillance of immune cells contribute of the nervous system contribute to the persistent microglial reactivity that we observe?Eric Topol (14:22):And do you have any hunch on what might be a successful worthwhile therapy to a candidate to test prospectively for this?Michelle Monje (14:30):I think it's too early to nominate candidates, but I think that the biology, the molecular and cellular biology is underscoring a role for particular cytokines and chemokines that are initiated by the immune response in the lung. And clear cellular targets, the goal I think the central goal being to normalize the neurovasculature and normalize microglial reactivity and so the question in this disease context and in others becomes, how can we kind of molecularly coach these reactive cells to go back to doing their normal jobs to being homeostatic? That's the challenge, but it's a surmountable challenge. It's one that I think that the scientific community can figure out, and it will be relevant not only to Covid, but also to many other consequences of immune challenges, including other post-infectious syndromes. It's not only Covid that causes long-term cognitive and other kinds of neurological and neuropsychiatric consequences. We saw this after the influenza pandemic in 1918. We've seen it after many other kinds of infectious challenges and it's important as we prepare for the next pandemic for the next global health challenge that we understand how the long-term consequences of an immune response to a particular pathogen play out.Eric Topol (15:58):No question and that I guess also would include myalgic encephalomyelitis and all the other post-infectious post viral syndromes that overlap with this. Now to switch gears, because that work is just by itself extraordinary but now there's this other field that you are a principal driver, leader, and that is cancer neuroscience. I didn't even know they had boards in neuro-oncology. I thought neurology was enough, but you got board certified in that too. This field is just exploding of interest because of the ability for cancer to cells to hijack neurons and neural circuits, which I guess the initial work goes way back but more recently, the fact that gliomas were just electrically charged. And so maybe you can frame this because this has not just amazing biology, but it's also introducing all sorts of therapeutic opportunities, including many ongoing trials.The Neuroscience of CancerMichelle Monje (17:08):Yes, yes and thank you for asking me about it. It's certainly one of my favorite things to think about, and perhaps as a bridge between the cognitive impairment that occurs after Covid and other inflammatory challenges and the neuroscience of cancer. I'll just highlight that maybe the common theme is it's important to understand the way cells talk to each other and that these sort of molecular conversations are happening on multiple scales and in unexpected ways, and they shape pathophysiology in a very important way. So continuing on that theme, we've known for many, many years, for decades in fact, that the nervous system and its activity shapes the development of the nervous system and actually it doesn't just shape the development of the nervous system where perhaps it's intuitive that the activity within the nervous system might sculpt the way that it forms, but it turns out that innervation is critical for development broadly, that innervation is necessary for organogenesis and that this is becoming clear in every organ that's been studied.(18:15):And so it stands to reason given that kind of perspective on the role that neuronal activity plays in normal development, plasticity, homeostasis, and regeneration of many different tissues, that the activity of the nervous system and those principles can be hijacked in the context of cancer, which is in many ways a disease of dysregulated development and regeneration. And so, I'm a neuro oncologist, I take care of children with a very terrible form of brain cancer called high-grade glioma and the most common form of high-grade glioma in kids occurs in the brain stem, it's called diffuse intrinsic pontine glioma (DIPG). It's really the worst disease you can imagine and understanding it has been the need to understand and treat it has been a guiding principle for me. And so, taking a big step back and trying to wrap my arms around the biology of these terrible high-grade gliomas like glioblastoma, like diffuse intrinsic pontine glioma, I wondered whether nervous system activity might influence cancer the way that it influences normal development and plasticity.(19:23):And as soon as we started to leverage tools of modern neuroscience like optogenetics to ask those questions to modulate the activity of neurons in a particular circuit and see how that influences cancer proliferation and growth, it was clear how very important this was, that active neurons and various subtypes very robustly drives the growth of these brain cancers. And so trying to understand the mechanisms by which that occurs so that we can target them therapeutically, it's become clear that the tumors don't just respond to activity regulated growth signals. They do. There are those paracrine factors, but that in brain cancer, the cancers actually integrate into the neural circuits themselves. That there are bonafide electrophysiological functional synapses that form between various types of neurons and high-grade glioma cells. We're discovering the same can occur in brain metastases from different organs, and that this principle by which neuronal activity drives the cancer is playing out in other tissues.(20:32):So right when we made these discoveries about glioma within this few years, discoveries were made in prostate cancer, in gastric cancer, colon cancer, skin cancer, pancreatic cancer. It seems that innervation is critically important for those tumor, and not just for their growth, but also for invasion metastasis, even initiation in diseases that are driven by particular oncogenes. There's an intersection between the power of those oncogenes to cause the cancer and the necessary environment for the cancer to form and that appears to also be regulated by the nervous system in very powerful ways. So, the exciting thing about recognizing this relatively unsettling feature of cancers is that as we understand it, the neuroscience of cancer becomes an entirely new pillar for therapy to combine with immunotherapy and more traditional cytotoxic therapies and we've been missing it until now. And so the opportunity exists now to leverage medicines that were developed for other reasons, for indications in neurology and cardiology and psychiatry medicines that target neurotransmitter receptors and ion channels that it turns out have a role in some forms of cancer. Now, each cancer has its own biology, so different types of neurons, different neurotransmitters, different neuropeptides play specific roles in that tissue context, but the principle is the same and so as we understand each cancer, we can start to understand what neuroscience inspired medicines we might leverage to better treat these tumors.Rewriting the Hallmarks of CancerEric Topol (22:17):Yeah, I mean it's amazing as a cardiologist to think that beta blockers could be used to help people with cancer and of course there are trials and some studies and particular cancers in that. One of the things that people maybe not outside of oncology don't follow these papers about hallmarks of cancer. There's been two editions, major editions of the hallmarks of cancer, and recently in the journal of cancer Cell, Douglas Hanahan and you wrote a classic about that the hallmarks need to be revised to include neuroscience. Maybe you could elaborate on that because it seems like this is a missing frontier that isn't acknowledged by some of the traditional views of cancer.Michelle Monje (23:08):Absolutely. So I think number one, I want to just give a shout out to Doug Hanahan and the role that the hallmarks of cancer, which is a review article that he wrote and has become sort of the Bible, if you will, of cancer biology really laying out common principles across cancer types that have provided a framework for us to understand this complex and diverse heterogeneous set of diseases. And so it was very exciting when he reached out and asked if I wanted to write this perspective, culminating nervous system interactions, neuroscience interactions as an emerging hallmark of cancer and as we examine them from that, we examine the neuroscience of cancer from that heuristic set of principles, this framework of principles of cancer biology, it's clear that there is a neural influence on the vast majority of them. We now understand from this exciting and burgeoning field that the nervous system can regulate cancer unregulated proliferation.(24:17):It promotes proliferation and growth. It promotes invasion and metastasis. It alters the immune microenvironment. It can both promote pro-tumour inflammation through neurotransmitter signaling. It can also help to modulate anti-tumor immunity. The crosstalk between immune cells, cancer cells and the nervous system are complex, profound, and I would argue incredibly important for immunotherapeutic approaches for cancer. At the same time that there are these diverse effects of the nervous system on cancer, cancer also influences the nervous system. And so, there's really this bidirectional crosstalk happening by which neurons in an activity dependent way, either in short range local neurons or in long range down a nerve or across a circuit, promote the pathophysiology of the cancer and you kind of know it's beneficial because the cancer does many different active things to increase innervation of the tumor. There is in a variety of different tissue context and disease states, elaboration of nervous system interactions through cancer derived either axonogenic or synaptogenic factors secretion, the nervous system remodels the nerves. It remodels the neural circuits to increase the connectivity of the nervous system with the cancer, and also to increase the activity of the nerves to increase the excitability of a neuron. And this contributes to not only driving the cancer, but to many of the really important symptoms that patients face with cancer, including tumor associated seizures as well as cancer associated pain.Eric Topol (26:07):Yeah, I mean this is actually so unusual to see a whole another look at what cancer is about. I mean, this is about as big a revision of thinking as I've seen at least in many, many years. The fact that you pulled this together about the new hallmarks also made me wonder because a number of years ago we went through this angiogenesis story whereby like this cancer can hijack blood vessels and promote it to growth. As you know very well, a lot of these anti-angiogenic efforts didn't go that well. That is they maybe had a small impact overall, but they didn't change the field in terms of success of therapy. I wonder if this is going to play out very differently. What are your thoughts about that? There's lots of shots on goal here and the trials have sprouted out very quickly to go after this.Michelle Monje (27:12):Yeah. I think it's important to recognize various microenvironmental effects on a cancer, including the nervous system effects as one piece of a puzzle that we need to put together in order to effectively treat the disease and I think to effectively treat a particularly very aggressive cancers, we need to hit this from multiple angles. Effective strategies will need to include targeting cell intrinsic vulnerabilities of the cancers as most traditional and targeted therapies are focused on doing right now together with decreasing the strong growth and metastasis influencing effects of the nervous system. I think that's one pillar of therapy that we really have been missing and that represents an important opportunity as well as leveraging the power of the immune system, which perhaps will only work optimally, particularly for solid tumors if you also address the nervous system influences on immune cells. And so I think that it's part of a holistic approach to effective therapy for tumors.(28:21):We have so far failed to treat with single agent or one dimensional kinds of approaches. We need to target not only the cell intrinsic vulnerabilities, the immunotherapeutic opportunities, and the nervous system mechanisms that are influencing all of that in really important ways. So I think it's important to design clinical research in the context of cancer neuroscience with that holistic view in mind. We don't think one strategy is going to be curative for difficult to treat tumors. I don't think that blocking neuron to glioma synapses in glioblastoma and DIPG will alone be sufficient but I do think it may be necessary for other therapies to work.Eric Topol (29:01):Yeah, I think that a perspective of in combination is extremely important. Now the overall, this a big fixation, if you will, about revving up immunotherapies various ways to do that. We'll talk about that in a moment, but without attention to the neurogenic side of this, that might be a problem. Now that gets me to the tumor type that you have put dedicated effort, which is this pediatric pontine tumor, which is horrendous, invading the brainstem and you've even done work with engineering T cells go after that. So you cover all the bases here. Can you tell us about where that stands? Because if you can prevail over that, perhaps that's one of the most challenging tumors of people there is.Diffuse Intrinsic Pontine GliomaMichelle Monje (29:54):Yeah, absolutely. So just a few words about this tumor, for those who don't know, diffuse intrinsic pontine glioma and other related tumors that happen in the thalamus and the spinal cord are the leading cause of brain tumor related death in kids. This is a universally fatal tumor type that tends to strike school age children and it's the worst thing I've ever seen in medicine. I mean, it really has been something that since I saw in medical school, I just have not been able to turn away from. And so studying it from many different perspectives, both the cell intrinsic vulnerabilities, the microenvironmental opportunities for therapy, and also the immunotherapeutic opportunities, it became clear to me that for a cancer that diffusely infiltrates the nervous system forms synapses with a circuit that it is invading and integrates into those circuits in the brainstem and spinal cord, that the only way to really effectively treat it would be a very precise and powerful targeted approach.(30:55):So immunotherapy was a very attractive set of approaches because in the best case, you have an engineered T cell or other immune cell that can go in and kind of like a special forces agent just find the T cells and disintegrate them from this synaptically integrated circuit that has formed. And so I began to search for cell surface targets on this particular type of cancer and found that one of the antigens for which many immunotherapy tools had already been made because it's prevalent in other kinds of cancer, was very highly expressed on diffuse midline gliomas, including diffuse intrinsic pontine glioma. And so this target, which is a sugar, actually it's a disialoganglioside called GD2, is extraordinarily highly and uniformly expressed on DIPG because the oncogene that drives DIPG and other related tumors, which is actually a mutation in genes encoding histone H3, which causes broad epigenetic dysregulation, strongly upregulates the synthesis genes for GD2.(32:05):And so it's a really ideal immunotherapeutic target on every cell, and it's at extraordinarily high levels. Again, speaking to the importance of collaboration, right when we made this discovery, one of the leaders in chimeric antigen receptor T cell therapy, CAR-T cell therapy named Crystal Mackall at Stanford and her offices is in my building, so I walked over and knocked on the door and said, do you want to work on this together? And so, we've been working together ever since and found that indeed CAR-T cells targeting GD2 cure our mice models, which is something I have never seen. I develop these models and have never seen anything that's effective, but it's always easier to help a mouse than to help a person and so we knew that the clinical translation would be challenging. We also knew that it would require intentionally causing inflammation in the brainstem that's already compromised neurocritical care.(33:07):I'm going to not use the word nightmare, but it's a set of challenges that we had to think about really carefully. We spent a lot of time and collaborated with our neurocritical care colleagues, our neurosurgical colleagues, and developed a protocol that had many, we anticipated this neurotoxicity of causing inflammation in the brain stem and we had many safety measures built in an anticipatory way, gave the therapy only in the intensive care unit and had many safeguards in place to treat anticipated hydrocephalus and other consequences of inducing inflammation in this particular region of the nervous system. Over the last four years, we began this trial at the beginning of the pandemic in June 2020 so that was its own unique set of challenges. We've seen some really incredibly exciting promising results we've presented. We've published some of our early experience, we're getting ready to present the larger experience.(34:14):And we've presented this at meetings. We've seen some kids go from wheelchair bound to walking in a matter of weeks. It's been just incredible and reduced to nearly nothing. Other kids have had less robust responses the therapy has really helped some kids, and it's failed others. And so we're working very hard right now to understand what factors affect this heterogeneity and response so that we can achieve durable and complete responses for every kid. I will tell you that my leading hypothesis right now is that it is the intersection of the immuno-oncology with the neuroscience that is modulating the response. Certainly, there are immune suppressive mechanisms, but there's also, I think, really important influences of neurotransmitters and neuropeptides on the immune response against central nervous system cancers in the central nervous system and so we're working hard to understand that crosstalk and develop strategies to optimize this promising therapy.(35:19):But it really has been one of the highlights of my professional life to see kids with DIPG and spinal cord diffuse midline gliomas get better even for a while, something I hoped at some point in my career to ever see and having seen it now so frequently in our trial patients, I'm really hopeful that this approach will be part of the answer. I'm hopeful for the future of immuno-oncology for solid tumors in general. I think when we understand the tumor microenvironment, we will be able to leverage these really powerful therapies in a better way.A Couple of Notable Neuroscientists!Eric Topol (35:58):Wow. Yeah, I mean, if anybody was to try to crack the case of one of the most challenging cancers ever seen, you would be that person. Now, speaking of collaboration, I didn't know this until I was getting ready to have the conversation with you, but your husband, Karl Deisseroth is like the optogenetics father. He is another exceptional rarefied leader in neuroscience. So, do you collaborate with him?Michelle Monje (36:35):We do collaborate, and in fact, so I met Karl when I was a medical student, and he was an intern in psychiatry so we go back a fair ways. We're both MD PhD students at Stanford, and we've been collaborating for many, many years in many different ways both in the clinic, I met him when I was a sub in neurology, and he was the psychiatry intern on neurology. We collaborated when he was a postdoc, and I was a graduate student on some neurobiological studies. We have four children. I have one stepson and four children that I can take full credit for and so we collaborated on five kids. For a while I really wanted, because he is such an amazing scientist, he's such a thought leader in neuroscience, as I started my own independent laboratory, I wanted to not be entirely in his shadow and so I did make it a point to do, I used optogenetics, but I took the course and bought the tools and did it all myself. I did the last questions at the dinner, but I really wanted to be kind of independent in the beginning. Now that my career and my laboratory is a bit more established, we are formally collaborating on some studies because he's a brilliant guy.Eric Topol (38:01):I think that you fit into that category too, and a bit more established is maybe the biggest understatement I've heard in a long time. The body of work you've done already at a young age is just beyond belief and you're on a tear to have big impact and many across the board. As you said, many things that you're learning about the brain with all of its challenges will apply to cancer, generally will apply to hopefully someday a treatment that's effective for Long Covid affects the brain and so many other things. So Michelle, I'm so grateful to have had this conversation. You are an inspirational force. You've covered a lot of ground in a short time and between you and your husband, I don't know that that's got to be the most dynamic duo of neuroscience that exists on the planet, in the human species, I guess. I just can't imagine what those kids of yours are going to do when they grow up.Michelle Monje (39:07):I'm biased, but they're pretty great kids.Eric Topol (39:10):Well, thank you for this and I think the folks that I get to listen to this will certainly get charged up. They'll realize the work that you're doing and the people you collaborate with and making cold calls to people. That's another story in itself that how you can get transdisciplinary efforts when you just approach somebody who's doing some good work. Another lesson just kind of hidden in our discussion. Thanks very much.Michelle Monje (39:40):Oh, thank you. It's wonderful to talk with you, Eric.*******************************************************Please share if your found this podcast informative Get full access to Ground Truths at erictopol.substack.com/subscribe

Pharma and BioTech Daily
Pharma and Biotech Daily: Your Source for Essential Updates in the Industry

Pharma and BioTech Daily

Play Episode Listen Later Nov 20, 2023 4:01


Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in the Pharma and Biotech world. In today's episode, we have several news updates to share with you. Let's get started.## FDA Official Janet Woodcock to RetireJanet Woodcock, a top official at the FDA, will be retiring early next year. Woodcock has been with the agency for an impressive 37 years and has played a crucial role in the FDA's pandemic response. She has also made important decisions regarding opioids, Alzheimer's therapy, and muscular dystrophy drugs.## Homology Enters Reverse Merger with Q32 BioBiotech company Homology has entered a reverse merger with Q32 Bio. This strategic move will result in a combined company operating under Q32's name. Homology recently faced challenges, including staff layoffs and halted research. This merger could potentially help them navigate through these difficulties.## Astellas Acquires Propella TherapeuticsAstellas, a pharmaceutical company, has made a significant acquisition by paying $175 million to acquire privately held Propella Therapeutics. This deal includes an experimental prostate cancer drug. This acquisition reflects the increasing activity in the biotech M&A space.## Eli Lilly Plans $2.5 Billion Manufacturing PlantEli Lilly, a major pharmaceutical company, has announced plans to build a new $2.5 billion manufacturing plant. This facility is aimed at meeting the growing demand for obesity drugs, following the recent approval of their obesity drug, Zepbound. The plant will help prevent shortages and ensure wider access to this drug.## Eli Lilly Invests in German Manufacturing FacilityContinuing on Eli Lilly's expansion plans, they are also investing $2.5 billion in a German manufacturing facility. This investment is specifically focused on meeting the high demand for weight-loss treatments. The German plant will support the supply of Tirzepatide, a drug that has shown promising results in clinical trials for obesity treatment.## AstraZeneca's Truqap Receives FDA ApprovalAstraZeneca's Akt inhibitor, Truqap, has received FDA approval. It can now be used in combination with the endocrine therapy Faslodex for adult patients with advanced HR-positive breast cancer. This approval expands the treatment options for breast cancer patients and provides a new targeted therapy approach.## FDA Approves Pfizer and Astellas' XtandiThe FDA has granted approval for Pfizer and Astellas' Xtandi. This drug can now be used for the treatment of nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis. This approval allows Xtandi to be used earlier in the treatment process, offering a new option for patients with this type of prostate cancer.## Merck's Keytruda Receives Expanded FDA ApprovalMerck has received FDA approval to expand the label of its anti-PD-1 blockbuster drug Keytruda. It can now be used as a first-line treatment option for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. This approval further solidifies Keytruda's position as a leading immunotherapy treatment.## Focus on Disease Prevention in Pharma IndustryThere is a growing conversation around disease prevention in the pharmaceutical industry. Many industry leaders, such as GSK CEO Emma Walmsley and 23andMe CEO Anne Wojcicki, are emphasizing the importance of prevention. GSK is focusing on its pipeline of vaccines, while 23andMe explores the potential of genomics in disease screening. This shift towards prevention comes at a time when life expectancy in the U.S. is declining due to preventable causes.That's all for today's episode. We hope you found these news updates informative and valuable. Stay tuned for more important updates in the Pharma and Biotech world. Thank you for listening to Pharma and Biotech Daily, the podcast that keeps you informed.

Answers in Genesis Ministries
Homology—Evidence for Evolution?

Answers in Genesis Ministries

Play Episode Listen Later Oct 14, 2023 1:00


Ken Ham on SermonAudio
Homology—Evidence for Evolution?

Ken Ham on SermonAudio

Play Episode Listen Later Oct 14, 2023 1:00


A new MP3 sermon from Answers in Genesis Ministries is now available on SermonAudio with the following details: Title: Homology—Evidence for Evolution? Subtitle: Answers with Ken Ham Speaker: Ken Ham Broadcaster: Answers in Genesis Ministries Event: Radio Broadcast Date: 10/13/2023 Length: 1 min.

Answers with Ken Ham
Homology—Evidence for Evolution?

Answers with Ken Ham

Play Episode Listen Later Oct 13, 2023


We see many similarities between living things. This is called “homology.” It's often used by evolutionists as evidence of descent from a common ancestor.

PaperPlayer biorxiv neuroscience
Spatially resolved cell atlas of the teleost telencephalon and deep homology of the vertebrate forebrain

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Jul 22, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.20.549873v1?rss=1 Authors: Hegarty, B. E., Gruenhagen, G. W., Johnson, Z. V., Baker, C. M., Streelman, J. T. Abstract: The telencephalon has undergone remarkable diversification and expansion throughout vertebrate evolution, exhibiting striking differences in structural and functional complexity. Nevertheless, fundamental features are shared across vertebrate taxa, such as the presence of distinct regions including the pallium, subpallium, and olfactory structures. Teleost fishes have a uniquely 'everted' telencephalon, which has made it challenging to compare brain regions in fish to those in other vertebrates. Here we combine spatial transcriptomics and single-nucleus RNA-sequencing to generate a spatially-resolved transcriptional atlas of the cichlid fish telencephalon. We then compare cell-types and anatomical regions in the cichlid telencephalon with those in amphibians, reptiles, birds, and mammals. We uncover striking transcriptional similarities between cell populations in the fish telencephalon and subpallial, hippocampal, and cortical cell populations in tetrapods. Ultimately, our work lends new insights into the organization and evolution of conserved cell-types and regions in the vertebrate forebrain. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv cell biology
Fusion of histone variants to Cas9 enhances homology-directed repair

PaperPlayer biorxiv cell biology

Play Episode Listen Later Jul 2, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.02.547417v1?rss=1 Authors: Kato-Inui, T., Ono, T., Miyaoka, Y. Abstract: As a versatile genome editing tool, the CRISPR-Cas9 system induces DNA double-strand breaks at targeted sites to activate mainly two DNA repair pathways: HDR which allows precise editing via recombination with a homologous template DNA, and NHEJ which connects two ends of the broken DNA, which is often accompanied by random insertions and deletions. Therefore, how to enhance HDR while suppressing NHEJ is a key to successful applications that require precise genome editing. Histones are small proteins with a lot of basic amino acids that generate electrostatic affinity to DNA. Since H2A.X is involved in DNA repair processes, we fused H2A.X to Cas9 and found that this fusion protein could improve the HDR/NHEJ ratio. As various post-translational modifications of H2A.X play roles in the regulation of DNA repair, we also fused H2A.X mimicry variants to replicate these post-translational modifications including phosphorylation, methylation, and acetylation. However, none of them were effective to improve the HDR/NHEJ ratio. We further fused other histone variants to Cas9 and found that H2A.1 exhibited the improved HDR/NHEJ ratio better than H2A.X. Thus, the fusion of histone variants to Cas9 is a promising option to enhance precise genome editing. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

@theorypleeb critical theory &philosophy
ŽIŽEK 101: The homology between Freud's Dream and Marx's Commodity | D&M S2:e13

@theorypleeb critical theory &philosophy

Play Episode Listen Later Feb 21, 2023 24:45


Mikey is back to teach Dave the basics of Žižek's theory of ideology.If you have been learning Lacan 101 and now Žižek through Mikey and Dave's conversations, you might want to dive into the deep end.Check out the course on Žižek's For They Know Not What They Do, which starts on February 25th: https://theory-underground.com/courses/ftknwtd/ABOUT / CREDITS / LINKSWelcome to the Theory Underground. Theory Underground aims to make challenging philosophical and theoretical work accessible, not by summarizing, but by aiding those who seek to engage in this work as a way of life. Interested in getting involved?Join the Theory Underground open forum today. Most of the forums are closed until certain readings or courses have been completed, but this is the one that is open! Welcome.https://theory-underground.com/forums/forum/MAIN Help beta trial this at https://theory-underground.com/Check out the courses, patron tiers and books, as well as events listed at these links:https://theory-underground.com/courses https://theory-underground.com/supporthttps://theory-underground.com//events Also the Theory Underground instagram and TikTok are both where it's happening: https://www.instagram.com/theory_underground/https://tiktok.com/@theory_undergroundMUSIC CREDITS Logo sequence music by https://olliebeanz.com/music https://creativecommons.org/licenses/by-nc-sa/4.0/legalcodeSong: Bust Down Artist: 808 DEATH CLUB License: Creative Commons Attribution 3.0 - http://bit.ly/RFP_CClicense

PaperPlayer biorxiv neuroscience
Persistent Homology-based Functional Connectivity Explains Cognitive Ability: Life-span Study

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Oct 21, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512619v1?rss=1 Authors: Ryu, H., Habeck, C. G., Stern, Y., Lee, S. Abstract: Brain-segregation attributes in resting-state functional networks have been widely investigated to understand cognition and cognitive aging using various approaches (e.g., average connectivity within/between networks and brain system segregation). While these approaches have assumed that resting-state functional networks operate in a modular structure, a complementary perspective assumes that a core-periphery or rich club structure accounts for brain functions where the hubs are tightly interconnected to each other to allow for integrated processing. We introduce a novel method, persistent homology (PH)-based functional connectivity, to quantify the pattern of information during the integrated processing. We also investigate whether PH-based functional connectivity explains cognitive performance and compare the amount of variability in explaining cognitive performance for three sets of independent variables: (1) PH-based functional connectivity, (2) graph theory-based measures, and (3) brain system segregation. Resting-state functional connectivity data were extracted from 279 healthy participants, and cognitive ability scores were generated in four domains (fluid reasoning, episodic memory, vocabulary, and processing speed). The results first highlight the pattern of brain-information flow over whole brain regions (i.e., integrated processing) accounts for more variance of cognitive abilities than either brain system segregation or the graph theory-based network topology measure. The results also show that fluid reasoning and vocabulary performance significantly decrease as the strength of the additional information flow on functional connectivity with the shortest path increases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Hacks For Life with Galon Jones
I'm Persuaded That Evolution Does Not Disprove Christianity, Pt 7

Hacks For Life with Galon Jones

Play Episode Listen Later Sep 6, 2022 23:24


Galon and Scott continue this series that discusses the belief that Evolution does not disprove Christianity. What evidence do the pro-evolution crowd provide to say evolution is true? Homology. Galon and Scott discuss. Join the conversation! #apologetics #christianity #bible #christian #god #christianapologetics #jesuschrist #truth #faith #gospel #christ #church #biblestudy #scripture #athiest #atheism #apologist #philosophy #morals #morality #desire #freewill #consciousness #evidence #soul #evolution #abiogenesis #youngearthcreationist #homology

Intelligent Design the Future
Darwin Visits the 21st Century–A Novella, Pt. 2

Intelligent Design the Future

Play Episode Listen Later Sep 2, 2022 21:50


Today's ID the Future from the vault continues the audio adaptation of Nickell John Romjue's fascinating novella, I, Charles Darwin. In this episode, Romjue's Darwin explores what we've learned about the fossil record since Darwin's time on Earth — and it's not what he expects. Part 1 of the audio series is here. To learn more and to purchase the book, visit www.icharlesdarwin.com. Source

Intelligent Design the Future
Emily Reeves Previews Dallas Science/Faith Conference 2022

Intelligent Design the Future

Play Episode Listen Later Jan 17, 2022 12:47


On this ID the Future, host Andrew McDiarmid sits down with Emily Reeves, one of the speakers for the January 22, 2022, Dallas Science and Faith Conference. The two walk through the lineup of speakers for the conference (Stephen Meyer, Brian Miller, Casey Luskin, Ray Bohlin, and others), tease some of the talks, and discuss how to join the one-day event live, either in person in the Dallas area or online. For more about the conference, slated for this Saturday, and to sign up, go here. Source

Intelligent Design the Future
Casey Luskin: Biogeography Is No Friend of Common Descent

Intelligent Design the Future

Play Episode Listen Later Jan 12, 2022 26:28


On this ID the Future, geologist Casey Luskin discusses biogeography and the problems it poses for the idea of universal common descent. To make it work, evolutionists have to propose, for instance, that old world monkeys rafted across the Atlantic from Africa to South America on a natural raft. Really? That's some raft. And how did the monkeys not starve to death? Or die of thirst? They couldn't drink salty ocean water, after all. And talk about a genetic bottleneck! That's just one of several problems Luskin raises with the idea that all species gradually evolved from a universal common ancestor. In his conversation with host Emily Reeves, he also touches on the problem of convergence, as when two creatures Read More › Source

Business Of Biotech
Turning The Liver Into A mAb Factory With Homology's Arthur Tzianabos, Ph.D.

Business Of Biotech

Play Episode Play 36 sec Highlight Listen Later Nov 15, 2021 50:12


Homology Medicines' approaches to gene therapy and gene editing have the potential to seriously disrupt both the cell/gene therapy space and the mAb manufacturing and administration paradigms as we know them. On this episode of the Business of Biotech, Homology President & CEO Arthur Tzianabos, Ph.D. shares the company's approach and supports its rationale for investing in its own development and manufacturing capacity. 

Bawdy Storytelling

Hey, It's an ugly word for a beautiful thing, so get back in there! Award winning science fiction essayist Meg Elison weaves a hypnotic true tale that takes us from Musicology to Entomology to Homology to Sexology, with a splash of playing doctor for good measure. Recorded live at the Courtyard Cabaret in San Francisco, this was Meg's first time on the Bawdy stage - but it won't be her last!  #LifeSciences #Inorganic #Epidermis #Scientist   Song: ‘Tattoo' (Girlfriends)   Episode Links Helix: Ready for better sleep? Helix Sleep has a quiz that takes just two minutes to complete and matches your body type and sleep preferences to the perfect mattress for you. Helix was awarded the #1 best overall mattress pick of 2020 and by GQ and Wired Magazine. Just go to HelixSleep.com/Dixie, take their two-minute sleep quiz, and they'll match you to a customized mattress that will give you the best sleep of your life.  Special Offer: right now, Helix is offering up to $200 off all mattress orders AND two free pillows to listeners of the Bawdy Storytelling podcast. That's HelixSleep.com/Dixie for up to 200 dollars off and two free pillows!   Like A Kitten: Has your sex fallen into the same old, dull routine? Break those boring habits with a fun sexy box from Like A Kitten. This month they're helping you choose your own adventure with their BYOB box. A.K.A., Build Your Own Box! You get to choose one item out of each of their 6 categories: Toys, Beauty Products, Lubes and Cleansers, Games, Sexy Accessories, and Lingerie. Within each category, you have 8 or more products you can choose from, so you can customize your kit. The box only costs $69, and some of the vibrators alone retail for more than that. & Right now, Like A Kitten is offering our listeners 20% off AND free shipping when you go to https://likeakitten.com/Dixie And/or enter the code Dixie at checkout. And I love that that a portion of all sales goes to charities that focus on women's empowerment, education, and health. So, you can feel good about feelin' good!   Patreon: Become a member of our Patreon community & You can get free livestream tickets, get access to all the livestream replays, be connected to other Bawdy fans, and so much more. Sign up for The Hookup ($10/month) or higher means that you receive free tickets to special events, Free tickets to our Livestream shows, access to the livestream replay, ad-free episodes of the podcast & more. Our Patreon has new patron tiers like the Confidante, the Concierge & more. Our Patrons have kept Bawdy going during COVID and as we struggle with re-entry, we're saying Thank you to all of you with Insider Info and exclusive access. While other events have gone away, Patreon (and you) are allowing us to continue to produce the Bawdy podcast, livestreams and live shows. We're offering great rewards on Patreon,  so become a Member Now at https://www.patreon.com/Bawdy   You can also Support Bawdy by sending your one-time donation to: Venmo: Venmo.com/BawdyStorytelling Paypal: BawdyStorytelling@gmail.com Zelle: BawdyStorytelling@gmail.com (& Thank You in advance!)   Want the perfect gift for your favorite Bawdy podcast fan? Dixie has created her own fragrance: You'll love #BawdyGotMeLaid perfume, scented with amber, ylang ylang, warm vanilla and golden honey. There's also our (scented or unscented) creamy Bawdy Butter, Hair & Bawdy Oil, & more. Bawdy Merchandise means you can deliver your own great smelling Motorboats while supporting Dixie and Bawdy. Get yours today at https://bawdystorytelling.com/merchandise Cameo/Custom Dixie video: Need the perfect gift? I've been having so much fun making customized videos for you! Send your friends and lovers a custom ‘Cameo' video from Dixie (with or without applause tiddies), it's a great way to send love from far away to a Bawdy fan… For just $69, you and I can have a short zoom call, you can tell me all about the recipient, and I'll make a custom video from you for their special day. Find out more by emailing dixie@BawdyStorytelling.com #CustomVideo #Gift   Ready to tell your story, and change your life? I'm now offering Storytelling for Self-Discovery to help you customize your stories. Anxious about navigating what's next? Are you writing a book, or working on your brand storytelling for your business?  No matter what you're up against, I can help you communicate with calmness & clarity - and I'd love to help you find your story. Email me at dixie@BawdyStorytelling.com for more info - we can book a short discovery call, and I'm happy to answer any questions.   Check out our Bawdy Storytelling Fiends and Fans group on Facebook - it's a place to discuss the podcast's stories with the storytellers, share thoughts with your fellow listeners, & help Dixie make the podcast even better. Just answer 3 simple questions and you're IN! https://www.facebook.com/groups/360169851578316/ Subscribe to our email list & you'll be notified of all upcoming Livestreams, Podcasts and Special Events first - it's at  https://bawdystorytelling.com/subscribe   Thank you to the Team that makes this podcast possible   Team Bawdy is:   Podcast Producer: Marty Garcia Sound Engineer: David Grosof Archivist / Video: Joe Moore Bawdy Livestream pre-show video by Donal Mooney Storytelling support by Mosa Maxwell-Smith & Bawdy Creator & Podcast Host Dixie De La Tour & Thank you to Pleasure Podcasts. Bawdy Storytelling is proud to be part of your sex-positive podcast collective! 

Intelligent Design the Future
Jonathan Wells and The Comprehensive Guide to Science and Faith, Pt. 1

Intelligent Design the Future

Play Episode Listen Later Oct 6, 2021 19:13


Today's ID the Future spotlights a new book, The Comprehensive Guide to Science and Faith: Exploring the Ultimate Questions about Life and the Cosmos, and specifically a chapter by biologist Jonathan Wells titled “What are the Top Scientific Problems with Evolution?” Wells is the guest, and the host is geologist and Center for Science and Culture associate director Casey Luskin, who co-edited the anthology from Harvest House Publishers. In this episode the first problem that Wells highlights concerns homology and convergence. A second problem involves fossils. Darwin anticipated “innumerable transitions” in the fossil record, but such a rainbow of transitional forms has never been found. Not even close. Another problem, molecular phylogenies. Another: the lack of observational evidence that natural Read More › Source

Theories of Everything with Curt Jaimungal
Dror Bar Natan on Knot Theory, Learning from Ed Witten, Eric Weinstein, and Quantum Field Theory

Theories of Everything with Curt Jaimungal

Play Episode Listen Later Sep 8, 2021 162:36


YouTube link: https://youtu.be/rJz_Badd43c Dror Bar-Natan is a Professor of mathematic who's interests include knot theory, QFT, and Khovanov homology Sponsors: https://brilliant.org/TOE for 20% off. http://algo.com for supply chain AI. Patreon: https://patreon.com/curtjaimungal Crypto: https://tinyurl.com/cryptoTOE PayPal: https://tinyurl.com/paypalTOE Twitter: https://twitter.com/TOEwithCurt Discord Invite: https://discord.com/invite/kBcnfNVwqs iTunes: https://podcasts.apple.com/ca/podcast/better-left-unsaid-with-curt-jaimungal/id1521758802 Pandora: https://pdora.co/33b9lfP Spotify: https://open.spotify.com/show/4gL14b92xAErofYQA7bU4e Subreddit r/TheoriesOfEverything: https://reddit.com/r/theoriesofeverything LINKS MENTIONED: PDF link of notes: https://tinyurl.com/4u4ru2yh TIMESTAMPS: 00:00:00 Introduction 00:03:29 Quantum Field Theory and Knot Theory 00:10:19 Another QFT / Knot Theory connection or analogy 00:20:46 Knot Theory and Gravity + Bar-Natan's PhD on Chern-Simons 00:24:08 Homology and Cohomology 00:32:54 Dror's average day / routines / laziness 00:35:23 What is "work" for a Professor? How much of it is thinking vs. reading etc.? 00:36:50 All the research is to support teaching 00:41:34 Motivated examples are what's missing in math teaching  00:47:35 Are you more creative when younger or older? 00:48:43 Being "systematic" with learning and research 00:50:37 Rant against theorems and proofs (emphasis) 00:54:51 What understanding a mathematical concept looks like 01:03:35 On laziness, strengths, and weaknesses in mathematics 01:07:47 Advice for the struggling mathematician 01:09:30 What did Dror learn from studying with Ed Witten 01:12:12 On Eric Weinstein 01:19:32 Knot Theory and Physics (again) 01:20:10 Why can't physics of 2 or 3 dimensions be extended to 4 easily? 01:34:21 Hard Problem of Consciousness 01:35:54 The problems Dror thinks about daily 01:37:49 What direction would he like mathematics research to head in? 01:40:26 Philosophy of math (ultra-finitism) 01:44:45 Pure mathematics in service to applied mathematics 01:47:14 How to learn a new field of mathematics 01:47:15 [the scientific mystical philosopher] Unreasonable effectiveness of mathematics 01:48:28 [Romain Gicquad] On IQ 01:51:06 [Tori Ko] ​What do you think about biology / psychology / philosophy 01:54:03 [Phill Thomas] What led him into the field of mathematics? Can anyone can learn advanced math? 02:03:52 [Tyler Goldstein] Do we need to make new research institutions not linked to academia? 02:06:04 Bias in academia 02:10:15 What's a mathematician? Who's a mathematician and who's not? 02:14:31 [Ashley Shipp] Does he think there is a connection between knot theory and protein folding? 02:19:49 [Jack Dysart] Is math a human construct? 02:22:50 [cx777o] Does he believe in a concept of god? 05:19:49 [Bill McGonigle] Ramanujan and his Goddess 02:23:47 Revealed story that Dror has about Curt and the Prisoner's Dilemma 02:30:27 [Harinivas P] Bible Code and applying advanced math in one's life 02:37:26 [Roy Dopson] Why does it take 360 pages to "prove" that 1+1=2? * * * Just wrapped (April 2021) a documentary called Better Left Unsaid http://betterleftunsaidfilm.com on the topic of "when does the left go too far?" Visit that site if you'd like to watch it.

Creation Magazine LIVE Podcast
Homology – do common structures imply common ancestor?

Creation Magazine LIVE Podcast

Play Episode Listen Later Aug 25, 2021 23:11


Similarity in living things is hailed as knock-down evidence for evolution. Find out why it actually powerfully supports Biblical creation.

Answers with Ken Ham
Homology—Evidence of Common Ancestry?

Answers with Ken Ham

Play Episode Listen Later Jun 2, 2021


Volume 141 of Answers with Ken Ham

Answers in Genesis Ministries
Homology—Evidence of Common Ancestry?

Answers in Genesis Ministries

Play Episode Listen Later Jun 2, 2021 1:00


ASC Workshops
Computing Khovanov-Rozansky homology

ASC Workshops

Play Episode Listen Later Apr 6, 2021 60:22


New perspectives on supersymmetric gauge theories

PaperPlayer biorxiv biochemistry
Crystal and solution structures reveal oligomerization of individual capsid homology domains of Drosophila Arc

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Nov 18, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.388496v1?rss=1 Authors: Hallin, E. I., Markusson, S., Bottger, L., Torda, A. E., Bramham, C. R., Kursula, P. Abstract: Synaptic plasticity is vital for brain function and memory formation. One of the key proteins in long-term synaptic plasticity and memory is the activity-regulated cytoskeleton-associated protein (Arc). Mammalian Arc forms virus-like capsid-like structures in a process requiring the N-terminal domain and contains two C-terminal lobes that are structural homologues to retroviral capsids. Drosophila has two isoforms of Arc, dArc1 and dArc2, with low sequence similarity to mammalian Arc, but lacking the mammalian Arc N-terminal domain. Both dArc isoforms have a capsid homology domain consisting of N- and C-terminal lobes. We carried out structural characterization of the four individual dArc lobe domains. As opposed to the corresponding mammalian Arc lobe domains, which are monomeric, the dArc lobes were all oligomeric in solution, indicating a strong propensity for homophilic interactions. The N-lobe from dArc2 formed a domain-swapped dimer in the crystal structure, resulting in a novel dimer interaction that could be relevant for capsid assembly or other dArc functions. This domain-swapped structure resembles the dimeric protein C of flavivirus capsids, as well as the structure of histones dimers, domain-swapped transcription factors, and membrane-interacting BAK domains. The strong oligomerization properties of the isolated dArc lobe domains explain the ability of dArc to form capsids in the absence of any large N-terminal domain, in contrast to the mammalian protein. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biochemistry
Mutagenesis and homology modeling reveal a predicted pocket of lysophosphatidylcholine acyltransferase 2 to catch Acyl-CoA.

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Nov 2, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.31.363515v1?rss=1 Authors: Hamano, F., Matoba, K., Hashidate, T., Suzuki, T., Miura, K., Hishikawa, D., Harayama, T., Yuki, K., Kita, Y., Noda, N. N., Shimizu, T., Shindou, H. Abstract: Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator that elicits various cellular functions and promotes several pathological conditions, including anaphylaxis and neuropathic pain. PAF is biosynthesized by two types of lyso-PAF acetyltransferases: lysophosphatidylcholine acyltransferase 1 (LPCAT1) and LPCAT2, which are constitutive and inducible forms of lyso-PAF acetyltransferase, respectively. Because LPCAT2 mainly produces PAF under inflammatory conditions, understanding the structure of LPCAT2 is important for developing specific drugs against PAF-related inflammatory diseases. Although the structure of LPCAT2 has not been determined, the crystal structure was reported for Thermotoga maritimaPlsC, an enzyme in the same enzyme family as LPCAT2. In this study, we identified residues in mouse LPCAT2 essential for its enzymatic activity and a potential acyl-coenzyme A (CoA)-binding pocket, based on homology modeling of mouse LPCAT2 with PlsC. We also found that Ala115 of mouse LPCAT2 was important for acyl-CoA selectivity. In conclusion, these results predict the structure of mouse LPCAT2. Our findings have implications for the future development of new drugs against PAF-related diseases. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biochemistry
Specificities of modeling membrane proteins using multi-template homology modeling

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Oct 23, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.22.351536v1?rss=1 Authors: Koehler Leman, J., Bonneau, R. Abstract: Structures of membrane proteins are challenging to determine experimentally and currently represent only about 2% of the structures in the ProteinDataBank. Because of this disparity, methods for modeling membrane proteins are fewer and of lower quality than those for modeling soluble proteins. However, better expression, crystallization, and cryo-EM techniques have prompted a recent increase in experimental structures of membrane proteins, which can act as templates to predict the structure of closely related proteins through homology modeling. Because homology modeling relies on a structural template, it is easier and more accurate than fold recognition methods or de novo modeling, which are used when the sequence similarity between the query sequence and the sequence of related proteins in structural databases is below 25%. In homology modeling, a query sequence is mapped onto the coordinates of a single template and refined. With the increase in available templates, several templates often cover overlapping segments of the query sequence. Multi-template modeling can be used to identify the best template for local segments and join them into a single model. Here we provide a protocol for modeling membrane proteins from multiple templates in the Rosetta software suite. This approach takes advantage of several integrated frameworks, namely RosettaScripts, RosettaCM, and RosettaMP with the membrane scoring function. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biochemistry
Homology Initialization for Protein Structure Determination via Distance Geometry

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Oct 15, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.339903v1?rss=1 Authors: Tasissa, A., Lai, R., Wang, C. Abstract: The problem of finding the configuration of points given partial information on pairwise inter-point distances, the Euclidean distance geometry problem, appears in multiple applications. In this paper, we propose an approach that integrates homology modeling and a nonconvex distance geometry algorithm for the protein structure determination problem. Preliminary numerical experiments show promising results. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv bioinformatics
Deep Homology-Based Protein Contact-Map Prediction

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Oct 5, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.04.325274v1?rss=1 Authors: Ronen, O., Zuk, O. Abstract: Prediction of Proteins' three-dimensional structure and their contact maps from their amino-acid sequences is a fundamental problem in structural computational biology. The structure and contacts shed light on protein function, enhance our basic understanding of their molecular biology and may potentially aid in drug design. In recent years we have seen significant progress in protein contact map prediction from Multiple Sequence Alignments (MSA) of the target protein and its homologous, using signals of co-evolution and applying deep learning methods. Homology modelling is a popular and successful approach, where the structure of a protein is determined using information from known template structures of similar proteins, and has been shown to improve prediction even in cases of low sequence identity. Motivated by these observations, we developed Periscope, a method for homology-assisted contact map prediction using a deep convolutional network. Our method automatically integrates the co-evolutionary information from the MSA, and the physical contact information from the template structures. We apply our method to families of CAMEO and membrane proteins, and show improved prediction accuracy compared to the MSA-only based method RaptorX. Finally, we use our method to improve the subsequent task of predicting the proteins' three-dimensional structure based on the (improved) predicted contact map, and show initial promising results in this task too - our overall accuracy is comparable to the template-based Modeller software, yet the two methods are complementary and succeed on different targets. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv bioinformatics
Embeddings from deep learning transfer GO annotations beyond homology

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Sep 6, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.04.282814v1?rss=1 Authors: Littmann, M., Heinzinger, M., Dallago, C., Olenyi, T., Rost, B. Abstract: Knowing protein function is crucial to advance molecular and medical biology, yet experimental function annotations through the Gene Ontology (GO) exist for fewer than 0.5% of all known proteins. Computational methods bridge this sequence-annotation gap typically through homology-based annotation transfer by identifying sequence-similar proteins with known function or through prediction methods using evolutionary information. Here, we proposed predicting GO terms through annotation transfer based on proximity of proteins in the SeqVec embedding rather than in sequence space. These embeddings originated from deep learned language models (LMs) for protein sequences (SeqVec) transferring the knowledge gained from predicting the next amino acid in 250 million protein sequences. Replicating the conditions of CAFA3, our method reached an Fmax of 37{+/-} 2%, 50{+/-} 3%, and 57{+/-} 2% for BPO, MFO, and CCO, respectively. This was numerically close to the top ten methods that had participated in CAFA3. Restricting the annotation transfer to proteins with

PaperPlayer biorxiv bioinformatics
Notable sequence homology of the ORF10 protein introspects the architecture of SARS-COV-2

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Sep 6, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.06.284976v1?rss=1 Authors: Hassan, S. S., Attrish, D., Ghosh, S., Pal Choudhury, P., Uversky, V. N., Uhal, B., Lundstrom, K., Rezaei, N., Aljabali, A. A. A., Seyran, M., Pizzol, D., Adadi, P., Abd El-Aziz, T. M., Soares, A., Kandimalla, R., Tambuwala, M., Lal, A., Azad, G. K., P. Sherchan, S., Baetas-da-Cruz, W., Palu, G., Brufsky, A. Abstract: The global public health is endangered due to COVID-19 pandemic, which is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Despite having similar pathology to MERS and SARS-CoV, the infection fatality rate of SARS-CoV-2 is likely lower than 1%. SARS-CoV-2 has been reported to be uniquely characterized by the accessory protein ORF10, which contains eleven cytotoxic T lymphocyte (CTL) epitopes of nine amino acids length each, across various human leukocyte antigen (HLA) subtypes. In this study, all missense mutations found in sequence databases were examined across twnety-two unique SARS-CoV-2 ORF10 variants that could possibly alter viral pathogenicity. Some of these mutations decrease the stability of ORF10, e.g. I4L and V6I were found in the MoRF region of ORF10 which may also possibly contribute to Intrinsic protein disorder. Furthermore, a physicochemical and structural comparative analysis was carried out on SARS-CoV-2 and Pangolin-CoV ORF10 proteins, which share 97.37% amino acid homology. The high degree of physicochemical and structural similarity of ORF10 proteins of SARS-CoV-2 and Pangolin-CoV open questions about the architecture of SARS-CoV-2 due to the disagreement of these two ORF10 proteins over their sub-structure (loop/coil region), solubility, antigenicity and change from the strand to coil at amino acid position 26, where tyrosine is present. Altogether, SARS-CoV-2 ORF10 is a promising pharmaceutical target and a protein which should be monitored for changes which correlate to change pathogenesis and clinical course of COVID-19 infection. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biophysics
Structural characterization of LsrK to target quorum sensing and comparison between X-ray and homology model

PaperPlayer biorxiv biophysics

Play Episode Listen Later Sep 3, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.03.281394v1?rss=1 Authors: Medarametla, P., Laitinen, T., Poso, A. Abstract: Quorum sensing is being investigated as an alternative therapeutic strategy in antibacterial drug discovery to combat bacterial resistance. LsrK is an autoinducer-2 kinase, playing a key role in the phosphorylation of autoinducer-2 (AI-2) signalling molecules involved in quorum sensing. Inhibiting LsrK could result in reduced pathogenicity by interfering with the quorum sensing signalling. Previously, we have generated homology models to identify LsrK inhibitors using structure-based virtual screening and successfully found the first class of LsrK inhibitors. While conducting these studies, the crystal structure of LsrK was released providing us an opportunity to inspect the reliability and quality of our models. Structural analysis of crystal structure and homology models revealed the consistencies of constructed models with crystal structure in the structural fold and binding site. Further, binding characteristics and conformational changes are investigated using molecular dynamics. These simulations provided us insights into the protein function and flexibility that need to be considered during the structure-based drug design studies targeting LsrK. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv biophysics
Peptide-based Inhibitors of Protein-Protein Interactions of Src Homology 2 Domain-Containing Phosphatase 2

PaperPlayer biorxiv biophysics

Play Episode Listen Later Aug 28, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.28.271809v1?rss=1 Authors: Bobone, S., Pannone, L., Biondi, B., Solman, M., Flex, E., Canale, V., Calligari, P., De Faveri, C., Gandini, T., Quercioli, A., Torini, G., Venditti, M., Lauri, A., Fasano, G., Hoeksma, J., Santucci, V., Cattani, G., Bocedi, A., Carpentieri, G., Tirelli, V., Sanchez, M., Peggion, C., Formaggio, F., Den Hertog, J., Martinelli, S., Bocchinfuso, G., Tartaglia, M., Stella, L. Abstract: Mutations of PTPN11, the gene coding for the Src homology 2 domain-containing phosphatase 2 (SHP2), cause childhood leukemias and developmental disorders. SHP2 inhibitors targeting the catalytic site or an allosteric pocket lack specificity or are ineffective on pathogenic variants. In addition, several data indicate that increased association with cognate proteins, through its SH2 domains, rather than enhanced catalytic activity, is the main effect of mutations causing hyperactivation of SHP2-mediated signaling. We developed peptide-based molecules with low nM affinity to the N-SH2 domain and high specificity. These molecules bind to pathogenic variants of SHP2 with an affinity up to 20 times higher than to the wild-type protein, in contrast to allosteric inhibitors, and were able to revert the effects of a pathogenic SHP2 mutation in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv bioinformatics
NetQuilt: Deep Multispecies Network-based Protein Function Prediction using Homology-informed Network Similarity

PaperPlayer biorxiv bioinformatics

Play Episode Listen Later Jul 31, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.30.227611v1?rss=1 Authors: Barot, M., Gligorijevic, V., Cho, K., Bonneau, R. Abstract: Transferring knowledge between species is challenging: different species contain distinct proteomes and cellular architectures, which cause their proteins to carry out different functions via different interaction networks. Many approaches to proteome and biological network functional annotation use sequence similarity to transfer knowledge between species. These similarity-based approaches cannot produce accurate predictions for proteins without homologues of known function, as many functions require cellular or organismal context for meaningful function prediction. In order to supply this context, network-based methods use protein-protein interaction (PPI) networks as a source of information for inferring protein function and have demonstrated promising results in function prediction. However, the majority of these methods are tied to a network for a single species, and many species lack biological networks. In this work, we integrate sequence and network information across multiple species by applying an IsoRank-derived network alignment algorithm to create a meta-network profile of the proteins of multiple species. We then use this integrated multispecies meta-network as input features to train a maxout neural network with Gene Ontology terms as target labels. Our multispecies approach takes advantage of more training examples, and more diverse examples from multiple organisms, and consequently leads to significant improvements in function prediction performance. Further, we evaluate our approach in a setting in which an organism's PPI network is left out, using other organisms' network information and sequence homology in order to make predictions for the left-out organism, to simulate cases in which a newly sequenced species has no network information available. Copy rights belong to original authors. Visit the link for more info

Dinosaurs Will Always Be Awesome
#DWABA 107 - *Extinctish | Avian Reconditioning Center

Dinosaurs Will Always Be Awesome

Play Episode Listen Later Jul 26, 2020 11:27


When we find fossils, they're often not complete.   How then, do scientists put together the full picture?  Jimmy breaks down the idea of Homology, and explores the evolution of dinosaurs in our art and museums!   Let's use what we've learned to build a life-sized dinosaur of our own!   While we're at it—let's meet some real live dinosaurs who need  your help!

PaperPlayer biorxiv biochemistry
Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Jul 23, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.23.217620v1?rss=1 Authors: Han, Y., Zhuang, Q., Sun, B., Lv, W., Wang, S., Xiao, Q., Chi, P., Pang, B., Zhou, Y., Wang, F., Wang, Q., Li, Z., Zhu, L., Li, F., Deng, D., Chiang, Y.-C., Li, Z., Ren, R. Abstract: Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-{Delta}4 structure, such as testosterone, androstenedione and progesterone, could be catalyzed by steroid 5-reductases (SRD5As) to generate their corresponding 3-oxo-5 steroids, which are essential for multiple physiological and pathological processes. Abnormal activities of SRD5As will lead to benign prostatic hyperplasia, alopecia, prostatic cancer or infertility due to the poor quality of sperms. However, the detailed reduction mechanisms of SRD5As remain elusive. Here we report the crystal structure of PbSRD5A, which shares 60.6% and 51.5% sequence similarities with human SRD5A1 and -2 respectively, from Proteobacteria bacterium in complex with the cofactor NADPH at 2.0 [A] resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic cavity for steroids substrates binding, whereas TM5-7 coordinate with cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with extensive biochemical characterizations, for the first time unveiled the substrate recognition of SRD5As and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-{Delta}4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible. One Sentence SummaryStructural and biochemical characterizations decipher the evolutionarily conserved mechanism in steroid 5-reductases catalyzing NADPH mediated steroids reduction. Copy rights belong to original authors. Visit the link for more info

PaperPlayer biorxiv genetics
Endogenous zebrafish neural Cre drivers generated by CRISPRCas9 short homology directed targeted integration

PaperPlayer biorxiv genetics

Play Episode Listen Later Jul 22, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.214452v1?rss=1 Authors: Almeida, M. P., Welker, J. M., Ekker, S. C., Clark, K. J., Essner, J. J., McGrail, M. Abstract: The Cre/lox recombinase system has been widely used for spatiotemporal control of gene expression in animal model systems, however, efficient methods to isolate zebrafish Cre drivers that reliably recapitulate endogenous expression patterns of known genes are in need. Here, we apply CRISPR/Cas9 double-strand breaks to direct targeted integration using short homology of a 2A-Cre recombinase transgene into the early coding region of proneural genes ascl1b, olig2 and neurod1. The pPRISM-2A-Cre targeting vector contains a linked lens-specific fluorescent secondary marker cassette for identification of transgenic embryos, and we observed high rates of germline transmission ranging from 10%-100% (2/20 olig2; 1/5 neurod1; 3/3 ascl1b). The established transgenic lines Tg(ascl1b-2A-Cre)is75, Tg(olig2-2A-Cre)is76, and Tg(neurod1-2A-Cre)is77 expressed functional Cre recombinase. in situ hybridization showed Cre expression reflected the pattern of the endogenous targeted proneural gene. In combination with Tg(ubi:loxP-EGFP-loxP-mCherry), each driver induced a switch from EGFP to mCherry expression in the expected proneural cell populations and their descendants, indicating efficient Cre-mediated recombination and excision of the floxed EGFP cassette. The results demonstrate Cre recombinase expression is driven by the native promoter and regulatory elements of the targeted genes. This approach provides a straightforward, efficient, and cost-effective method to generate cell type specific zebrafish Cre drivers whose spatial and temporal restricted expression mimics endogenous genes, surmounting the challenges associated with promoter BAC cloning and transposon mediated transgenesis. Copy rights belong to original authors. Visit the link for more info

What does it mean to be Colombian?

Podcast about homology

Creation Magazine LIVE Podcast
Examining evidence for evolution and deep time

Creation Magazine LIVE Podcast

Play Episode Listen Later May 22, 2020 25:14


Evidence for evolution from many fields has been thoroughly refuted but continues to be taught. We summarize key refutations from areas including: Vestigial organs, Junk DNA, Humans and chimp DNA 99% similar, Homology, Human embryos go through evolutionary stages, Transitional fossils, Pakicetus, Tiktaalik, Ape-men, Human evolution, Radiometric dating, Distant starlight.

Sense Makes Math presents: Meet a Mathematician
East VS West/Math VS Physics/Habilitation/New Book!-Meet a Mathematician (010): Pavel Mnev

Sense Makes Math presents: Meet a Mathematician

Play Episode Listen Later Jul 1, 2019 69:02


Pavel Mnev is an Assistant Professor of Mathematics at the University of Notre Dame. He was awarded his Ph.D. in Mathematical Physics in 2008 from the St. Petersburg Department of Steklov Mathematical Institute at the Russian Academy of Sciences under the supervision of Acad L. D. Faddeev. He was awarded the Andre Lichnerowicz prize in Poisson Geometry in 2016, and has previously worked at the Max Planck Institute for Mathematics in Bonn, Germany.His research is in mathematical physics, more precisely he is interested in the interactions of quantum field theory with topology, homological/homotopical algebra and supergeometry.His website is here: https://www3.nd.edu/~pmnev/We would like to thank Pavel for being on our show "Meet a Mathematician" and for sharing his stories and perspective with us!www.sensemakesmath.comPODCAST: http://sensemakesmath.buzzsprout.com/TWITTER: @SenseMakesMathPATREON: https://www.patreon.com/sensemakesmathFACEBOOK: https://www.facebook.com/SenseMakesMathSTORE: https://sensemakesmath.storenvy.comSupport the show (https://www.patreon.com/sensemakesmath)

Believing The Bible
05/11/19 - Homology

Believing The Bible

Play Episode Listen Later May 13, 2019 12:30


Mentors at Your Benchside
Designing Flanking Homology DNA Assembly Experiments

Mentors at Your Benchside

Play Episode Listen Later Nov 15, 2017 60:57


Join us in this webinar on demystifying DNA assembly. In this webinar, you will learn: - How flanking homology DNA assembly methods work - How to use web-based software to design experimental methods for flanking homology DNA assembly methods - How synthetic DNA fragments fit in to the DNA assembly process Dr. Nathan Hillson will discuss methods in flanking homology DNA assembly, including Gibson, In-Fusion, and yeast TAR assembly—amongst many other related methods. Current DNA assembly methods offer many advantages over traditional (multiple cloning site, digestion/ligation) approaches, including the ability to assemble multiple fragments at once, the lack of a necessary specific restriction enzyme, and time commitment. One part of DNA assembly is designing these experimental methods. To that end, Dr. Hillson will provide a demonstration of how to use web-based software to automate and optimize the design of protocols for these methods. Finally, Dr. Hillson will explain how synthetic DNA fragments fit in to the DNA assembly process and how this relates to your work.

Palaeo After Dark
Podcast 108 - Homology Party

Palaeo After Dark

Play Episode Listen Later Apr 16, 2017 95:01


In this episode, the gang decides to go back to some old papers they enjoy to discuss the concept of homology. What do we really mean when we say certain characteristics are shared due to evolutionary history? Also, for a brief minute in the second half, James was spontaneously possessed by demonic spirits that made him spout nonsense he doesn't actually believe. Unrelated to this, he also had a splitting migraine.  Up-goer Five (Amanda in a fever-based fugue state edition):  Today our friends talk about how things are the same because animals are brother and sister. This means that the brother and sister animals have parts that are the same because they have the same mother and father animals. But the way that brother and sister animals have the same parts can be because of different ways. People do not understand really what it means when we say that these brother and sister animals have the same parts. So our friends try to explain how these parts came to be and why. References: Van Valen, Leigh M. "Homology and causes." Journal of Morphology 173.3 (1982): 305-312. Wiley, E. O. "Homology, identity and transformation." Mesozoic fishes 4 (2008): 9-21.

DJ Mickey
HOMOLOGY (Sydney Mardi Gras 2017 Podcast)

DJ Mickey

Play Episode Listen Later Feb 1, 2017 74:26


HOMOLOGY həˈmɒlədʒi (n) The similarity of a structure or function of parts of different origins based on their descent from a common evolutionary ancestor. We all share a common ancestry & genetics. We are all human. We are all equal. I'm so honoured to be playing at this year's Sydney Gay & Lesbian Mardi Gras Party and to get everyone warmed up ive released this podcast for EVERYONE to enjoy. This years MG Festival theme is "Creating Equality" and although all humans are equal no matter what sexuality, gender, nationality, race or religion, we all have different tastes which makes us unique. HOMOLOGY is a collection of some of my favourite new house tracks and some of my favourite classic house tracks remixed with influences from pop & western culture, LGBT culture, middle eastern and tribal cultures and many more. Whether you want to lip sync to Ariana, Britney and Whitney, Vogue and get C*UNT, or "cut sick" to some tribal bangers, HOMOLOGY is a 1 hour journey for everyone who loves life and to celebrate the diversity, fun and freedom that the Sydney Mardi Gras Festival will bring in 2017. Available for download on www.djmickey.com.au See you at the party!

DJ Mickey
HOMOLOGY (Sydney Mardi Gras 2017 Podcast)

DJ Mickey

Play Episode Listen Later Jan 31, 2017 74:26


HOMOLOGY həˈmɒlədʒi (n) The similarity of a structure or function of parts of different origins based on their descent from a common evolutionary ancestor. We all share a common ancestry & genetics. We are all human. We are all equal. I'm so honoured to be playing at this year's Sydney Gay & Lesbian Mardi Gras Party and to get everyone warmed up ive released this podcast for EVERYONE to enjoy. This years MG Festival theme is "Creating Equality" and although all humans are equal no matter what sexuality, gender, nationality, race or religion, we all have different tastes which makes us unique. HOMOLOGY is a collection of some of my favourite new house tracks and some of my favourite classic house tracks remixed with influences from pop & western culture, LGBT culture, middle eastern and tribal cultures and many more. Whether you want to lip sync to Ariana, Britney and Whitney, Vogue and get C*UNT, or "cut sick" to some tribal bangers, HOMOLOGY is a 1 hour journey for everyone who loves life and to celebrate the diversity, fun and freedom that the Sydney Mardi Gras Festival will bring in 2017. Available for download on www.djmickey.com.au See you at the party!

DJ MKY
HOMOLOGY - (Mardi Gras 2017)

DJ MKY

Play Episode Listen Later Jan 26, 2017 74:26


HOMOLOGY həˈmɒlədʒi (n) The similarity of a structure or function of parts of different origins based on their descent from a common evolutionary ancestor. We all share a common ancestry & genetics. We are all human. We are all equal. I'm so honoured to be playing at this year's Sydney Gay & Lesbian Mardi Gras Party and to get everyone warmed up ive released this podcast for EVERYONE to enjoy. This years MG Festival theme is "Creating Equality" and although all humans are equal no matter what sexuality, gender, nationality, race or religion, we all have different tastes which makes us unique. HOMOLOGY is a collection of some of my favourite new house tracks and some of my favourite classic house tracks remixed with influences from pop & western culture, LGBT culture, middle eastern and tribal cultures and many more. Whether you want to lip sync to Ariana, Britney and Whitney, Vogue and get C*UNT, or "cut sick" to some tribal bangers, HOMOLOGY is a 1 hour journey for everyone who loves life and to celebrate the diversity, fun and freedom that the Sydney Mardi Gras Festival will bring in 2017. Available for download on www.djmickey.com.au See you at the party!

RARECast
Why Homology Medicines Might Be a Game Changer for Gene Therapy

RARECast

Play Episode Listen Later Jul 6, 2016 16:32


Gene therapy is offering rare disease patients the promise of delivering potential cures, but as it is generally approached today it has technical challenges to overcome, manufacturing complexities, and an expected high cost. Homology Medicines is taking a unique approach to gene therapy that makes use of a special set of viral vectors that gets around many of the obstacles other gene therapies face. We spoke to Arthur Tzianabos, CEO of Homology Medicines, about the company’s gene therapy, how it’s unique, and why its production and cost may be similar to other biologics today.

Biochemistry (BIO/CHEM 4361) - Fall 2015
9pre. Pre-Lecture on Sequence Homology from Primary Structure

Biochemistry (BIO/CHEM 4361) - Fall 2015

Play Episode Listen Later Oct 19, 2015 21:22


Biochemistry (BIO/CHEM 4361) - Fall 2015
9pre. Pre-Lecture on Sequence Homology from Primary Structure

Biochemistry (BIO/CHEM 4361) - Fall 2015

Play Episode Listen Later Oct 19, 2015 21:22


BioAcoustica Talks Podcast
Ward Wheeler: Arthopods, history and homology: morphology and molecules.

BioAcoustica Talks Podcast

Play Episode Listen Later Oct 7, 2015


The inaugural (1999) Frederick W. Edwards lecture held at the Natural History Museum, London, supported by the Royal Entomological Society.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 05/06

Searching sequence databases and building 3D models for proteins are important tasks for biologists. When the structure of a query protein is given, its function can be inferred. However, experimental methods for structure prediction are both expensive and time consuming. Fully automatic homology modeling refers to building a 3D model for a query sequence from an alignment to related homologous proteins with known structure (templates) by a computer. Current prediction servers can provide accurate models within a few hours to days. Our group has developed HHpred, which is one of the top performing structure prediction servers in the field. In general, homology based structure modeling consists of four steps: (1) finding homologous templates in a database, (2) selecting and (3) aligning templates to the query, (4) building a 3D model based on the alignment. In part one of this thesis, we will present improvements of step (2) and (4). Specifically, homology modeling has been shown to work best when multiple templates are selected instead of only a single one. Yet, current servers are using rather ad-hoc approaches to combine information from multiple templates. We provide a rigorous statistical framework for multi-template homology modeling. Given an alignment, we employ Modeller to calculate the most probable structure for a query. The 3D model is obtained by optimally satisfying spatial restraints derived from the alignment and expressed as probability density functions. We find that the query’s atomic distance restraints can be accurately described by two-component Gaussian mixtures. Moreover, we derive statistical weights to quantify the redundancy among related templates. This allows us to apply the standard rules of probability theory to combine restraints from several templates. Together with a heuristic template selection strategy, we have implemented this approach within HHpred and could significantly improve model quality. Furthermore, we took part in CASP, a community wide competition for structure prediction, where we were ranked first in template based modeling and, at the same time, were more than 450 times faster than all other top servers. Homology modeling heavily relies on detecting and correctly aligning templates to the query sequence (step (1) and (3) from above). But remote homologies are difficult to detect and hard to align on a pure sequence level. Hence, modern tools are based on profiles instead of sequences. A profile summarizes the evolutionary history of a given sequence and consists of position specific amino acid probabilities for each residue. In addition to the similarity score between profile columns, most methods use extra terms that compare 1D structural properties such as secondary structure or solvent accessibility. These can be predicted from local profile windows. In the second part of this thesis, we develop a new score that is independent of any predefined structural property. For this purpose, we learn a library of 32 profile patterns that are most conserved in alignments of remotely homologous, structurally aligned proteins. Each so called “context state” in the library consists of a 13-residue sequence profile. We integrate the new context score into our Hmm-Hmm alignment tool HHsearch and improve especially the sensitivity and precision of difficult pairwise alignments significantly. Taken together, we introduced probabilistic methods to improve all four main steps in homology based structure prediction.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Monitoring homology search during DNA double-strand break repair in vivo

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06

Play Episode Listen Later Sep 12, 2013


Thu, 12 Sep 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16945/ https://edoc.ub.uni-muenchen.de/16945/1/Renkawitz_Joerg.pdf Renkawitz, Jörg ddc:570, ddc:500, Fakultät für Biologi

Grothendieck-Teichmüller Groups, Deformation and Operads
Factorization homology of topological manifolds

Grothendieck-Teichmüller Groups, Deformation and Operads

Play Episode Listen Later Apr 5, 2013 62:00


Francis, J (Northwestern University) Tuesday 02 April 2013, 11:00-12:00

Grothendieck-Teichmüller Groups, Deformation and Operads
(Co)homology theories and deformation theory

Grothendieck-Teichmüller Groups, Deformation and Operads

Play Episode Listen Later Feb 4, 2013 108:00


Vallette, B (Université de Nice Sophia Antipolis) Wednesday 30 January 2013, 14:00-15:30

Moduli Spaces
Hilbert schemes of singular plane curves and HOMFLY homology of their links

Moduli Spaces

Play Episode Listen Later Apr 18, 2011 57:49


Shende, V (Princeton) Thursday 14 April 2011, 15:00-16:00

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06
Context-specific methods for sequence homology searching and alignment

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06

Play Episode Listen Later Dec 13, 2010


Mon, 13 Dec 2010 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16691/ https://edoc.ub.uni-muenchen.de/16691/1/Biegert_Andreas.pdf Biegert, Andreas ddc:540, ddc:500, Fakultät für Chemie und Pharmazie

Fakultät für Geowissenschaften - Digitale Hochschulschriften der LMU
Homology Modeling of Toll-Like Receptor Ligand-Binding Domains

Fakultät für Geowissenschaften - Digitale Hochschulschriften der LMU

Play Episode Listen Later May 26, 2010


Toll-like receptors (TLRs) are in the front-line during the initiation of an innate immune response against invading pathogens. TLRs are type I transmembrane proteins that are expressed on the surface of immune system cells. They are evolutionarily conserved between insects and vertebrates. To date, 13 groups of mammalian TLRs have been identified, ten in humans and 13 in mice. They share a modular structure that consists of a leucine-rich repeat (LRR) ectodomain, a single transmembrane helix and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. Most TLRs have been shown to recognize pathogen-associated molecular patterns (PAMPs) from a wide range of invading agents and initiate intracellular signal transduction pathways to trigger expression of genes, the products of which can control innate immune responses. The TLR signaling pathways, however, must be under tight negative regulation to maintain immune balance because over-activation of immune responses in the body can cause autoimmune diseases. The TLR ectodomains are highly variable and are directly involved in ligand recognition. So far, crystal structures are missing for most TLR ectodomains because structure determination by X-ray diffraction or nuclear magnetic resonance (NMR) spectroscopy experiments remains time-consuming, and sometimes the crystallization of a protein can be very difficult. Computational modeling enables initial predictions of three-dimensional structures for the investigation of receptor-ligand interaction mechanisms. Computational methods are also helpful to develop new TLR agonists and antagonists that have therapeutic significance for diseases. In this dissertation, an LRR template assembly approach for homology modeling of TLR ligand-binding domains is discussed. To facilitate the modeling work, two databases, TollML and LRRML, have been established. With this LRR template assembly approach, the ligand-binding domains of human TLR5-10 and mouse TLR11-13 were modeled. Based on the models of human TLR7, 8 and 9, we predicted potential ligand-binding residues and possible configurations of the receptor-ligand complex using a combined procedure. In addition, we modeled the cytoplasmic TIR domains of TLR4 and 7, the TLR adaptor protein MyD88 (myeloid differentiation primary response protein 88) and the TLR inhibitor SIGIRR (Single immunoglobulin interleukin-1 receptor-related molecule) to investigate the structural mechanism of TLR negative regulation.

GRASP Lecture Series: Geometry, Representations, and some Physics
K-homology and index theory IV: The Baum-Connes Conjecture

GRASP Lecture Series: Geometry, Representations, and some Physics

Play Episode Listen Later Jan 28, 2010 74:47


These talks will be about the C*-algebra approach to index theory and K-theory that was proposed by Atiyah and worked out in detail by Kasparov. In the last lecture I'll discuss the most famous application of Kasparov's work - to the Novikov higher signature conjecture and the Baum-Connes conjecture. I'll sketch the proof of both conjectures for Gromov's a-T-menable groups (these are groups that act properly on an infinite-dimensional Euclidean space, and include amenable groups, free groups, Coxeter groups and others). The argument uses an interesting noncommutative C*-algebra that serves as a proxy for the commutative algebra of continuous functions on a Euclidean space (which isn't itself very useful when the space is infinite-dimensional). This algebra, together with a closely related Bott-Dirac operator on the Euclidean space, may have other applications.

GRASP Lecture Series: Geometry, Representations, and some Physics
K-homology and index theory III: Applications of K-homology

GRASP Lecture Series: Geometry, Representations, and some Physics

Play Episode Listen Later Jan 26, 2010 76:50


These talks will be about the C*-algebra approach to index theory and K-theory that was proposed by Atiyah and worked out in detail by Kasparov. What is K-homology good for? I'll try to answer with examples in this and the previous talks. There is an obvious connection to the Atiyah-Singer index theorem, and roughly speaking K-homology provides a context in which to consider the index theorem's many elaborations. A general theme is that while two operators may look rather different, for example when studied using a symbol calculus, functional analysis and the framework of K-homology can sometimes give a means to identify their Fredholm index theories.

GRASP Lecture Series: Geometry, Representations, and some Physics
K-homology and index theory II: Geometric K-homology and the index theorem

GRASP Lecture Series: Geometry, Representations, and some Physics

Play Episode Listen Later Jan 21, 2010 72:15


These talks will be about the C*-algebra approach to index theory and K-theory that was proposed by Atiyah and worked out in detail by Kasparov. What is K-homology good for? I'll try to answer with examples in this and the following talks. There is an obvious connection to the Atiyah-Singer index theorem, and roughly speaking K-homology provides a context in which to consider the index theorem's many elaborations. A general theme is that while two operators may look rather different, for example when studied using a symbol calculus, functional analysis and the framework of K-homology can sometimes give a means to identify their Fredholm index theories.

GRASP Lecture Series: Geometry, Representations, and some Physics
K-homology and index theory I: K-theory from the viewpoint of functional analysis

GRASP Lecture Series: Geometry, Representations, and some Physics

Play Episode Listen Later Jan 19, 2010 69:05


These talks will be about the C*-algebra approach to index theory and K-theory that was proposed by Atiyah and worked out in detail by Kasparov. Atiyah pointed out that an elliptic operator on a manifold can be viewed as cycles for the homology theory that is dual to K-theory. This led him to suggest a functional-analytic definition for K-homology, and Kasparov later worked out the complete theory. In the first talk I shall tell more of this story.

Darwin and Evolution - for iPad/Mac/PC
Transcript -- Shared ancestries

Darwin and Evolution - for iPad/Mac/PC

Play Episode Listen Later Mar 1, 2009


Transcript -- Exhibits at the Natural History Museum in Tring reveal a striking shared ancestry between the hippo and the dolphin.

Darwin and Evolution - for iPad/Mac/PC

Exhibits at the Natural History Museum in Tring reveal a striking shared ancestry between the hippo and the dolphin.

Darwin and Evolution - for iPod/iPhone

Exhibits at the Natural History Museum in Tring reveal a striking shared ancestry between the hippo and the dolphin.

Darwin and Evolution - for iPod/iPhone
Transcript -- Shared ancestries

Darwin and Evolution - for iPod/iPhone

Play Episode Listen Later Mar 1, 2009


Transcript -- Exhibits at the Natural History Museum in Tring reveal a striking shared ancestry between the hippo and the dolphin.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
Functional Characterisation of Two Channels Proteins Involved in Leguminous Symbiosis

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06

Play Episode Listen Later Dec 18, 2008


Legume-rhizobial symbiosis results in the formation of a new organ, the nitrogen-fixing root nodule. A chemical communication between both partners accompanies the invasion of plant host cells by bacteria and the development of the root nodule. In response to plant-released flavonoids, rhizobia produce lipo-chito-oligosaccharide signalling molecules, so called Nod factors. Early signal transduction in legumes such as Lotus japonicus and Medicago truncatula, is associated with a succession of tightly orchestrated ion fluxes across different membrane systems of the host cell. The Nod factor perception at the plasma membrane triggers Ca2+ oscillations that are associated with the nucleus. CASTOR and POLLUX are required for Ca2+ spiking. Homology modeling suggested CASTOR and POLLUX might be ion channels. However, experimental confirmation was lacking. Therefore we performed biochemical and electrophysiological analysis to define their role. Here we show that CASTOR and POLLUX form two independent homocomplexes in the nuclear rim in planta. We reconstituted CASTOR in planar lipid bilayers and electrophysiological measurements revealed that CASTOR is a cation channel preferentially permeable to potassium. The permeability of the sequence-related POLLUX for cation could be as well demonstrated through expression of POLLUX in different yeast mutants. Furthermore, we demonstrate that a voltage-dependent magnesium blocking mechanism contributes to reduce the conductance of CASTOR at negative membrane potential. By screening a L. japonicus roots cDNA library using yeast-two-hybrid system, a SNF7 protein interacting with CASTOR was found which acts as positive regulator in the nodulation pathway. Collectively the data demonstrate that both CASTOR and POLLUX are nuclear localized cation channels. Therefore, we propose that CASTOR and POLLUX may act as counter ion channels to facilitate a rapid efflux of charge associated with the calcium efflux. Alternatively and not mutually exclusive, they may catalyze a nuclear membrane depolarization leading to the activation of calcium channels responsible for calcium spiking

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06
The role of Src-homology 2 domain containing tyrosine phosphatase 2 in growth factor dependent endothelial signalling and angiogenesis

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later May 24, 2007


Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in proliferation, survival and sprouting of human microvascular- and umbilical vein endothelial cells (HMEC, HUVEC) using antisense oligonucleotides (AS-ODN) and a pharmacological SHP-2 inhibitor (PtpI IV). Knock-down of SHP-2 decreased bFGF and PDGF dependent endothelial cell proliferation (p

Genomics & Computational Biology
Lecture 07B: Protein 1: 3D Structural Genomics, Homology, Catalytic and Regulatory Dynamics, Function & Drug Design

Genomics & Computational Biology

Play Episode Listen Later Apr 25, 2007 42:33


This course will assess the relationships among sequence, structure, and function in complex biological networks as well as progress in realistic modeling of quantitative, comprehensive, functional genomics analyses. Exercises will include algorithmic, statistical, database, and simulation approaches and practical applications to medicine, biotechnology, drug discovery, and genetic engineering. Future opportunities and current limitations will be critically addressed. In addition to the regular lecture sessions, supplementary sections are scheduled to address issues related to Perl, Mathematica and biology.

Genomics & Computational Biology
Lecture 07A: Protein 1: 3D Structural Genomics, Homology, Catalytic and Regulatory Dynamics, Function & Drug Design

Genomics & Computational Biology

Play Episode Listen Later Apr 25, 2007 61:52


This course will assess the relationships among sequence, structure, and function in complex biological networks as well as progress in realistic modeling of quantitative, comprehensive, functional genomics analyses. Exercises will include algorithmic, statistical, database, and simulation approaches and practical applications to medicine, biotechnology, drug discovery, and genetic engineering. Future opportunities and current limitations will be critically addressed. In addition to the regular lecture sessions, supplementary sections are scheduled to address issues related to Perl, Mathematica and biology.

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Identification of novel nuclear factors required for chloroplast gene expression and photosystem I assembly

Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06

Play Episode Listen Later Jul 14, 2005


During evolution of photoautotrophic eukaryotes, the nucleus has gained a dominant role in the coordination of the integrated genetic system of the cell consisting of three specifically coevolved genetic compartments. The photosynthetic machinery is encoded by the chloroplast and nuclear genomes. Therefore, biosynthesis and assembly of stochiometric amounts of subunits as well as association of the proteins with corresponding cofactors need to be managed and precisely regulated. To identify novel nuclear-encoded factors involved in the regulation of chloroplast gene expression at different levels, 12 nuclear mutants with high chlorophyll fluorescence (hcf) phenotypes denoting quite diverse defects in the photosynthetic apparatus were selected. Three of them, hcf145, hcf109 and hcf101, were analysed and the affected genes were characterized in more detail. Spectroscopic, fluorimetric and immunological studies have revealed that hcf145 and hcf101 were predominantly affected in photosystem I (PSI), while hcf109 had pleiotropic deficiencies. Remarkably, the dramatic reduction of PSI core complex accumulation in hcf145 was not accompanied by corresponding deficiencies of the outer light-harvesting antenna complex. A comparison of stationary transcript levels with rates of transcription, as estimated by Northern and chloroplast run-on transcription analysis, revealed that the hcf145 mutant is primarily and specifically characterised by a reduced stability of tricistronic chloroplast psaA-psaB-rps14 transcripts. The corresponding operon encodes the two large PSI polypeptides PsaA and PsaB, which form the heterodimeric PSI reaction centre, and the ribosomal protein S14. Chloroplast translation inhibition experiments excluded translational defects as the primary cause of impaired mRNA stability. Defined intervals of the tricistronic transcript were quantified by real-time RT-PCR which established that the psaA region is less stable than the rps14 region in hcf145. Therefore, although up to date, no 5'-3' exoribonucleases have been found in eubacteria (including the ancestors of plants), factor HCF145 appears to be required for the protection of the psaA-psaB-rps14 mRNA against progressive ribonucleolytic degradation starting at the 5' end. In the hcf109 mutant, exclusively plastid transcripts containing UGA stop codons are unstable. The affected gene encodes the first described chloroplast peptide chain release factor AtprfB. Its full-length cDNA, introduced into hcf109 via Agrobacterium-mediated transformation, could functionally complement the mutant. Homology of AtprfB to eubacterial release factors indicates that processes of translational termination in chloroplasts resemble those in eubacteria. The mutant phenotype revealed that translation of all plastid mRNAs containing UGA stop codons is exclusively terminated by AtprfB. However, besides its peptide chain release function, AtprfB appears to acquire yet unknown roles in regulating the stability and translation of the chloroplast mRNAs containing UGA stop codons. These additional regulatory functions could reflect evolutionary constraints which keep the number of plastid TGA stop codons high in vascular plant organelles in contrast to those of algae, mosses and ferns. In contrast to hcf145, steady-state levels and translation of photosynthetic transcripts are not altered in the PSI mutant hcf101. Separation of thylakoid membrane complexes by sucrose gradient centrifugation has uncovered that, similar to hcf145, accumulation of the outer antenna of PSI is not changed in hcf101. Therefore, hcf101 is affected in the assembly of the PSI core complexes. Expression of the HCF101 full-length cDNA in the hcf101 genetic background functionally complemented the mutant. The HCF101 protein encodes a very ancient and universally conserved protein of P-loop ATPases. HCF101 is plastid-localised and represents the first described factor essentially required for the assembly of PSI and other [4Fe-4S]-containing protein complexes in the chloroplast. Relatives of HCF101 are divided into four classes present in all organisms and in all cellular compartments. The antiquity of HCF101 points to the importance of Fe-S cluster biogenesis during the earliest phases of cell evolution. The ubiquity of HCF101 indicates that it is essential for all free-living cells.

Chemie und Pharmazie - Open Access LMU - Teil 02/02
A yeast gene (BLH1) encodes a polypeptide with high homology to vertebrate bleomycin hydrolase, a family member of thiol proteinases

Chemie und Pharmazie - Open Access LMU - Teil 02/02

Play Episode Listen Later Jan 1, 1993


We have purified bleomycin hydrolase from yeast (molecular mass 55 000 Da). Using protein sequence-derived degenerate oligonucleotide primers and amplification by polymerase chain reaction, the yeast gene BLH1 was isolated and characterized. The deduced amino acid sequence (483 amino acids) exhibits surprisingly high homology to vertebrate bleomycin hydrolase (43% identical residues and 22% conserved exchanges). It contains three blocks of sequences found conserved in other members of the thiol proteinase family and thought to be associated with the catalytic centre. BLH1 is non-essential under all growth conditions tested. However, in the presence of 3.5 mg bleomycin/ml medium wild-type cells have a slight growth advantage compared to blh1 mutant cells.

family members yeast vertebrates homology polypeptide chemie und pharmazie