Hip osteoarthritis is a degenerative and painful disorder. The disease affects an estimated 21% of the population between the ages of 45 and 54, and twice that fraction among people over 75. Nearly half of cases of hip osteoarthritis can be traced to femoral acetabular impingement, the growth of extra bone over the hip joint. The progression from impingement to osteoarthritis is believed to be mediated by the release of inflammatory molecules across the hip cartilage, but the exact mechanisms are unknown. To address this gap, researchers tracked levels and patterns of inflammatory markers and cartilage from patients with symptoms of impingement. Their findings highlight the role of inflammation in upsetting joint homeostasis. The research team examined full thickness cartilage samples gathered from the zone of impingement in 45 patients undergoing hip surgery. Reasons for surgery fell into one of three groups, early disease, late disease or hip dysplasia. Early disease referred to symptomatic CAM impingement, which describes the overgrowth of bone across the femoral head, whereas late disease was defined as advanced osteoarthritis secondary to CAM impingement. Patients undergoing treatment for hip dysplasia were included for comparison, as dysplasia represents a degradation mechanism different from that of impingement. Samples from seven young adult donors served as controls. Early or late disease cartilage showed worse degenerative changes than cartilage from hips with dysplasia. These included poorer structure, lower cell counts, lower amounts of cartilage supporting proteins, and a blurring of the normally distinct boundary between hard and soft cartilage. The variation suggested that impingement elicits an inflammatory response in articular cartilage. To find out, the team then examined the expression of inflammatory molecules in the different samples. The two groups of hips showing signs of impingement exhibited unique patterns of inflammation. Compared with hips with dysplasia and control hips, they expressed higher concentrations of inflammatory and degradative proteins, such as interleukin 1 beta, acytokine involved in osteoarthritis, matrix metalloprotonase 13, an enzyme linked to tissue remodeling, and atoms 4, an enzyme associated with cartilage degradation in osteoarthritis. To be sure, hips with dysplasia did express the same molecules, but their expression was confined to the superficial zone of cartilage. In hips with impingement, these molecules were expressed in all cartilage zones. This more extensive pattern suggests that inflammation due to impingement results from chronic shear stress. Overall, these findings hint at the possibility that molecular inflammation in the hip could be a mechanism that links CAM impingement to osteoarthritis. Further clinical and translational studies are needed to determine whether and how surgical treatment could improve joint health in patients with hip impingement.


Hi, and welcome to the FlowGrow experience.  Hello and welcome. This morning we're having the live chatters with Sam Vakneen. Sam is a professor in psychology and he is author of the book Malignant Self-Love Narcissism Revisited, published in 1999. Sam has coined the phrase and was first to coin the phrase narcissistic abuse in the early 90s. He is one of the world's leading spokesperson on narcissistic personality disorder and really has the academic background and backing knowledge to back it. Good morning Sam, how are you? Good morning Sam, how are you? Good morning, thank you for having me. Yeah, I've been I've been watching your work now for some time and I find it quite striking and I find it rather controversial. A lot of what you talk about is is controversial and I suppose narcissism is one of those things. It's a topic, it's a very current topic and it's a word that's thrown around a lot. But you define narcissism in a certain way that's unlike everybody else and you know how other people are using it. It seems to be used as an umbrella term to describe all-round selfishness but through your work I've kind of ascertained that there's something more to narcissism than that and it goes a bit deeper. Do you want to share a little bit about narcissism and what it means to you? It's not what it means to me, it's what we teach in universities.  Narcissism is a healthy variant and a pathological variant. The healthy variant underlies self-esteem, self-confidence and a well-regulated sense of self-worth. The pathological variant is probably a compensation compensatory, it compensates for a deep-set sense of inferiority and inadequacy. Now the compensation can take various forms as the grandiose form of the overt narcissism. The overt narcissism is not aware of any compensatory effect, he really believes his own inflated self-image and self-perception and then there's the covert narcissist who is more attuned to the fact that he's compensating for a lack for a deficiency. We are beginning to think that the overt narcissist is actually a subspecies of the psychopath. It's a psychopathic kind of mutation and the covert narcissist, the compensatory narcissist, seems to be the only real narcissist. At any rate these are people who try to project an image of perfection, brilliance, infallibility and then try to convert you to this missionary religion, private religion, trying to make you confirm and affirm that their view of themselves is not counterfactual, is not fallacious, but it's true and if you don't agree to collaborate in this charade then they shred you, they punish you and abuse you and torment you until you do. So it's a coercive tactic. So it's a kind of a mind dance. So once we start to engage with narcissism or a narcissistic personality we engage in a mind dance. I've heard you describe co-dependence as kind of a hidden narcissist. You know that they're hidden in some way because they're colluding with the narcissistic kind of affair. Can you tell me a little bit about that? So there has to be, like for the narcissist to exist there has to be another, right? There has to be like somebody to, like so if one is God there has to be a worshiper, right? Well yes, but a worshiper doesn't have to be a co-dependent. Co-dependent, some co-dependents, not all of them by a long stretch, but some co-dependents are attracted to narcissists. Majority of borderline, people with borderline personality disorder are attracted to narcissists, but the narcissist is indiscriminate and promiscuous in his choice of mate, in his mate selection.  It is grandiose, it is grandiose of victims to assume otherwise. Victims simply can't digest the fact that they're utterly interchangeable and dispensable and indistinguishable and commodified, they can't digest this. So they aggrandize themselves by saying that they are special, that they are empaths and super empaths and galactic, intergalactic empaths and other such total nonsense, total unmitigated nonsense. It's a form of self-aggrandizement because when the narcissist does to you, he reduces you to dust, interchangeable dust modes.  You're just providing with the narcissist with what he needs and you are really, really indistinguishable from your predecessors and your successors. The narcissist forgets you the minute you're no longer useful or functional. And many, many, many victims, the vast majority of victims, I would say, are actually unable to assimilate this and to accept this. So they're creating this morality place and these narratives where the narcissist had targeted them or they were special in some way or, but it's all clinically unsupported by any evidence and it's sheer unmitigated nonsense. So when you're talking there, I have an image of, you know, the Joker and Harley Quinn, you know, this kind of dynamic. But I just wanted to ask you a little bit about narcissistic supply.   How can an individual just see another person as a source of resource, as a source for resources, rather than an actual human? How does this come about this severing of empathy, so to speak, or, you know, thankfulness even? I think we're all, we've all become like this. I think we have all become consumers of other people and what they can afford us, what they can give to us. I think this used to be an outlier or an aberration, maybe 30 or 40 years ago. But I think it's the commonality right now. I think everyone, definitely the younger generations, people under the age of 35, everyone regards other people as service providers, functionalities, and everyone makes the calculus of what's in it for me, and why do I stand to gain from that? Then how far am I willing to sacrifice or compromise my resources? And what is the exchange here? Am I being played? Am I getting the upper hand? So relationships nowadays are power plays, glorified power plays. And I'm sorry to say that the typical relationship that used to prevail 40 years ago when I was young is no longer in existence. I'm hard pressed to find such an example anymore. People are transactional. They negotiate and then they transact to have a relationship. Intimacy is threatening relationships, ominous. People regard relationships as a double whammy. On the one hand, relationships obstruct, impede, and destroy careers. So it's either career or relationships. You have to choose.  It's still a form of abuse. So people say to themselves, especially the young, especially people under the age 35, they say to themselves, why on earth would I want this? Why would I want a relationship? According to studies by Q Center between 2019 and 2022, people today regard relationships as much less desirable than a career. Careers are regarded as 2.2 times more desirable than having a relationship. In other words, if people have to choose between a career and a relationship, two-thirds of the time, they're likely to opt for a career in lieu of having a relationship. That's the situation today. So catching feelings is a bad thing for you. It's like a virus. You don't want to catch feelings.  That's why between 45% and 60% of adults in industrialized societies are lifelong singles. That's why 31% of adults never had an intimate relationship. That's why 45% of adults never had sex in a committed relationship. These are the new figures. This is the situation right now. We don't trust each other. It's the age of distrust. So narcissistic supply has become the norm. Yeah. So you're just kind of, I know you've described narcissism as a, it's kind of like a culture of discard. It's like once use is no longer of use, that something becomes discarded. And how you're describing society there is one of discard, that people no longer place an emphasis on the value of contact or connection or the warmth of of, you know, togetherness or like, you know, how do you feel about that? How do you feel about like that change in value that like you described how it was when you were younger? You know, do you feel that this is a value of value of benefit to our society or do you feel it should change? We are a consumerist society. So we consume people the way we consume smartphones and so on. And there's new version, a new version every year. So we discard people and move on to the new version. Some of us discard people after one night, you know, one night stand. About 22% of all adults engage exclusively in one night stands. They don't have anything longer than one night stand. These people are called socio sexually unrestricted. But this is their lifestyle. They put an emphasis on career and work and accomplishments, and they have sex exclusively with strangers in one night stands. Now, as a consumerist society, we place emphasis on growth, economic growth, I mean. So we measure our well-being and our happiness in terms of economic growth individual and societal. So, for example, we are very concerned with GDP growth, growth of gross domestic product. We are very concerned with inflation because inflation retards growth. It sort of diminishes the value of our earnings. So our consuming power is reduced. We are very, very concerned with economic questions with money issues, with wealth accumulation and formation. And we are very, very terrified of sharing. Sharing means diminishment. If you share, you are less, not more. And so sharing has become an anathema. And relationships are about sharing. So they have become a threat. And feelings lead to relationships. So people avoid feelings by, for example, drinking. They drink in order to avoid feelings, in order to avoid feelings, especially when they have sex. So drinking today is coupled with sex. It's inextricably associated with sex. Well over 82% of sexual encounters today take place after heavy drinking. So there's no question of right and wrong in psychology or even in other fields of the humanities. There's a question of efficacious or not efficacious. In other words, is this an efficient way to live? And the answer is no, it's not an efficient way to live. Because for example, the rate of depression had tripled. The rate of anxiety disorders had quintupled. Suicides have gone up 50%, especially by the way among teenage girls. Yeah, we have those statistics here also. Yeah. So it's killing us. Simply it's killing us. It may be efficient on the level of society as a whole in terms of money, in terms of wealth formation. It definitely is very, very helpful to the elites, the economic elites, the financial elites. There are 10,000 people. That's 10,000, not 10 million. There are 10,000 people who together hold 51% of the wealth of the planet.  When you're single, you have a lot more time to watch YouTube. When you're single, you have a lot more time to be on Facebook and that translates to money. They are monetizing your eyeballs. These people want you to be single. They don't want you to have an intimate relationship. They don't want you to have a family. Today economic growth and capitalism had become the avowed enemies of mental health and mental welfare. It's as simple as that. You have to choose. You have to make a choice. And yet you have an insurgent of research online for attachment, attachment disorder and relationship, your attachment style, people looking for solutions and relationship, looking for advice. It's one of the biggest markets online, relationship advice, relationship counsel. People are looking for that. They're looking for connection. They're looking for content, contact. I know in Ireland we have one of the highest rural isolation rates in Europe. People suffer greatly from loneliness. It's a kind of a symptom of this age of distraction. I know that people have a yearning. There is a yearning for contact and for relationship and for reaching out. I just think that it's that people don't really know how to perhaps change the system as it exists. And I know that there is a huge insurgence of new age and new age communities that have become deviant. I suppose they're not following mainstream and they're reverting to the romanticism of paganism and going back to the old ways. But I don't think that that's necessarily going to do it either. What do you feel can fill this vacuum? And how can we even address capitalism or this age of distraction and the emptiness it's created within society and people? For every person who is looking for intimacy and relationship advice, there are 10 people who are looking to be a victim. Victimhood is the big, the big game, much bigger game. People are invested in identity politics in victimhood because they begin to constitute an integral part of their new identities. They form a worldview. Victimhood had become a worldview, a way to interpret the world, to imbue it with meaning, to make sense of what's happening. In an age of uncertainty, irrationality, conspiracy theories and victimhood are the staples. They've always been throughout human history. So I don't think people are really looking for relationships because had people been looking for relationships, they would not have been a collapse of 50% in marriages. The marriage rate has gone down 50% since 1980. Relationships have collapsed utterly. Well over 45% of adults in industrialized societies are singles. So these are choices. There's an inability to compromise. There's a total lack of intimacy skills and relationship skills. So people, I think we call this in psychology action substitution. If you don't really want to have a relationship, what you do instead, you research relationships. And that gives you the feeling that you're doing something about relationships. But you're not. Rather than go out there and risk vulnerability and risk pain and embrace hurt as an engine of growth and development, which is what mature adults do. The infantile adults of today sit at home alone with Netflix and a pet and they do research. They surf the internet. They join forums and they discuss relationships day in and day out, night in and night out, rather than actually engage in relationships, rather than do, you know, a consultant is someone who failed as a doer. So people are much more into advice and support and feeling a victim and castigating and criticizing and echo chambering and the loneliness gap is ever growing and long before the pandemic, but long before the pandemic people don't have relationships. They are afraid. People are terrified.  But would you not say that a lot of it has to do with the conditioning that we grow up with, you know, that lack that that we haven't learned how to communicate, you know, correctly, you know, I find that in relationship and engagement and it can be just an intimate relationship or it could be in, you know, everyday relationships, a lot of the problems that arise within relationships is often our inability to communicate, you know, what's vulnerable. And there's so many different perceptions out there. So many different mindsets, so many different ways of looking. But I think most of the time trouble arises when people can't communicate their needs, their wants, their, their true feelings. Do you know? There are several basic problems, but problem number one is risk aversion. Simply risk aversion. There's nothing more risky in life than having a relationship.  Nothing is more threatening than a relationship. You need to really be brave to have a relationship. And most people today are risk averse. They are risk averse medically. They are risk, they, the insurances of thriving business. I mean, we are, everything is built around mitigating risk. And when something happens, we are infuriated. How did we let it happen? And everything must have a solution. And if it doesn't have a solution, someone is to blame and we need to decapitate him. So we are in this risk averse situation, and, and relationships fell victim to this. The second thing is we look around and we see other people's marriages. Nothing to write home about. Other people's marriages are miserable. The models, the classical models of relationship had failed, had failed. And the younger generations have a look at their parents' marriages and their grandparents' marriages and they're not impressed. And so they avoid, they avoid the mistakes of their elders. They don't understand that the fault is not with the institution. The fault was with the psychological dynamics of the people who had entered into these contracts, marital contracts and relationship contracts. There is a process of infantalization. A process of infantalization first described in the 1940s. It's been 80 years. It's been ongoing for 80 years. We are, we are regressing. Puberty starts three years later today than in the 1980s, according to Twenge and Campbell and other scholars. So Puberty starts three years later and it ends a whopping 10 years later. So today people are adolescents until age 25. Clinically, that's how we define adolescence. And one third to one half, depending on the country, live with their parents, cohabit with their parents until age 35. I repeat this incredible number. Until age 35, one third to one half still cohabit with their parents and rely financially on their parents. Now people say, yeah, but that's a very difficult period. There's been the great recession and there's been COVID. May I remind this spoiled Bratish generation that there was World War II. There was the great depression and they were much worse than anything life is throwing at us today. And yet no one at that time thought of parasiting on their parents. No one at that time thought of not having a relationship. These are excuses. These generations are spoiled because they had never had to fight for a living and they had never had to fight for their lives in a war. They have a lot of money, too much money and they have the unconditional support of their parents. Their parents are incapable of loving them so they give them money. And so we have generations of Bratish, temper tantrum, spoiled, corrupted people who are incapable of having relationships with themselves, let alone with other people. Yeah, okay. So yeah, no, I would tend to agree that on that level that people do tend to stay at home with their families way too long. And I do think that helicopter parenting and, you know, kind of over protective parenting has a lot to do with that. But just getting back to narcissism and, you know, what creates a narcissist?  Because from listening to your videos, I feel that it's something to do with, you know, discard or not being wanted or rejected. And this creates something within an individual if the foundation is right or if the environment is right for narcissism to grow and develop. As far as I ascertained, narcissism is something to do with the defense structure. But you describe it as an emptiness within and that the narcissist is completely empty. Can you expand a little bit on that? Yeah, none of the... First of all, we have been described... We have been discussing narcissism to this very minute. We've never strayed. It's all narcissism. Everything I've described is narcissism. These people who are unable to form relationships, they're narcissistic. There are studies that show that narcissism among college students, for example, has skyrocketed. These are narcissists. It's a narcissistic society and civilization. And we are witnessing the impacts of narcissism. Moreover, narcissism is now glorified and glamorized. They are scholars who think that narcissism is wonderful. Only two days ago, the leading psychologist in Russia came out and said, we should all be narcissists. We should envy narcissists. They should be our role models. In 2016, new scientists published a cover story, parents teach your children to be narcissists. Scholars like Kevin Dutton and Makobi and so on, they use the term, the phrase, high functioning narcissists. They think narcissism is a great thing. It's the next evolutionary step. We are glorifying and glamorizing narcissism. We are even electing narcissists to political positions. The president of the United States, the president of Brazil, narcissists are taking over. Narcissists are taking over because we envy them and we want to be like them. So we have been discussing narcissism to this very second. We've never strayed. Pathological narcissism is a reaction to any bridge of emerging boundaries in the child. When the child is not allowed to separate from the parents and to become an individual without fear of punishment, then we have a narcissist. Now, the bridge of boundaries can be in two vectors, in two ways. One way is by spoiling the child, idolizing the child, pedestalizing the child, instrumentalizing the child regarding the child as an instrument of gratification and parentifying the child, forcing the child to act as a parent. So in all these cases, the child is not allowed to separate from the parent. The alternative is the classical forms of abuse, sexual abuse, physical abuse, psychological abuse. These are also exemplars. These are also examples of bridge of boundaries because this kind of abuse, sexual abuse, for example, is a total bridge of boundaries, bodily and mental. So all these forms of misparenting or dead parenting or not good enough parenting, all these forms lead to to pathological narcissism. Narcissism is a defense mechanism that part is true. And it is a form of private religion where the child creates an imaginary friend within an imaginary universe known as a paracrossan. And he creates an imaginary friend and that imaginary friend is everything the child is not. That imaginary friend is omnipotent or powerful, all-knowing, omniscient. That imaginary friend is brilliant and perfect and lovable and blameless and flawless and blemishless. At the same time, the child is receiving messages from the parent, I'm going to love you only if you perform. I'm going to love you only if you conform to my expectations. So this is conditional love. The imaginary friend that the child creates, known as the false self, provides the child with unconditional acceptance and with protection because it's godlike. Because it's godlike, the child needs to effectuate human sacrifice. Like every primitive religion, this divinity, this newly newfangled deity that the child comes up with demands human sacrifice. So the child sacrifices the only human it has access to himself. The child sacrifices himself. This is known as the true self. So child gets reads of the true self and fully identifies with the false self. Henceforth, for the rest of the life of the narcissist, there's an emptiness or a void or a black hole where the true self used to be. And there's an external apparition, the false self, which the narcissist mistakes for himself. Moreover, the narcissist, because he commits this mistake of regarding a figment of his imagination as reality. And then identifying with this external figure, the false self, the narcissist continues to do this in all his future relationships. He breaches his intimate partner's boundaries. He does not allow her to separate. He regards her as an extension. And he confuses her external existence with her representation in his mind known as introject. So he begins to interact not with her, but with her representation in his mind. I call it snapshot. Can I break that down? I've heard you talk about the snapshot. So the snapshot is like basically he has an idea of her. He has an idea of what she is.  Am I getting that right? Think of it this way. There's a photo and then the narcissist photoshopped the photo. That's the process of idealization. Now he's doing this because if he has an ideal partner, it reflects on him favorably. If he succeeded to secure an ideal partner, infinitely beautiful, drop dead gorgeous, amazingly intelligent, then it says something about him, doesn't it? So he idealizes himself actually by idealizing her. And so he creates this photograph of her. Literally. That's why I call it snapshot.   He refuses to accept this. And when she begins to diverge or deviate from the snapshot, she becomes a threat, what we call a persecutory object. And then he begins to hate her. And then he devalues her. He says she has changed. I don't know what happened to her. And then because he can't admit that he has committed a mistake. So it's not his fault. Something has happened to her. She had been corrupted or changed or something, influenced maybe.  His inner universe is populated with his avatars of everyone significant in his life. And so if one of these avatars proves to be false, it casts in doubt all the other avatars. It's very, very threatening. It's life threatening. So the need to devalue and discard is a survival strategy. So what does that hide then? What's that space hiding? Like what's behind that space? Why be afraid of that? Why be afraid of that dislocation? What's behind that space? If we go back to the narcissist's childhood, the narcissist ironically had been abandoned by the very parents who had not allowed him to separate. When the parent does not allow the child to separate, they prevent the child. They don't allow the child to evolve, to grow, to develop. In other words, they don't love the child. So it's a form of abandonment, ironically. The merger and the fusion, what we call the symbiosis, the merger and the fusion with the parent implies an abandonment of the child. Because the parent's implicit message is, you don't exist.  You are an extension of me. You have no separate existence. So it's like killing the child. It's a form of assassination. And so there is a huge, a tremendous underlying separation in security. That's the clinical term for abandonment anxiety. The narcissist is afraid to be, again, rejected, abandoned and so on. In this sense, narcissists are not very dissimilar to people with borderline personality disorder. Kernberg in 1975 had suggested this, that they are actually variants of the same thing. And so the narcissist is exactly like the borderline. He's terrified of abandonment, but his solution is different. The borderline solution to abandonment anxiety is to project herself onto the intimate part. So the intimate partner becomes dominant and she becomes his extension. The narcissist solution is exactly the opposite. He becomes dominant and the intimate partner becomes his extension. That's why narcissists fit perfectly with borderlines. The borderline wants to become an extension and the narcissist loves to convert it into an extension because the minute you become a photograph, the minute you become an avatar, you are forever mine. You will never abandon me because you're in my mind and I'm in full unmitigated control of my mind. And the minute you deviate, the minute you deviate from this, you're threatening me.  And so narcissists keep testing you all the time. Will you really abandon me? I'm going to behave egregiously. I'm going to misbehave.  I'm going to torture you. I'm going to humiliate you. I'm going to do everything inconceivable to you. I'm going to test you. Do you really love me unconditionally despite all my misconduct?  It's kind of looking for a divine mother, a divine, omnipotent mother. Not necessarily divine and omnipotent, the narcissist role, but a mother. Yes, a mother figure. To that level of unconditional love, yeah, it's quite divine. The mother he never had. No, good enough mothers provide unconditional love, all good enough mothers. So the mother he never had is trying to parentify his partners. He's trying to convert them into maternal figures. By the way, not only women, for example, when the narcissist is engaged in a business transaction, he has a business partner. He's going to convert the business partner into maternal figure. Moreover, the narcissist acts as a maternal figure in the love bombing stage, in the grooming stage.  And I love you unconditionally. So the narcissist in the initial phases of every shared fantasy, which is the only form of relationship, intimate relationships that narcissists have, narcissists can engage only in shared fantasies. There's no other form. In 1989, this was first described by a psychologist called Sander, so it's not my invention.   You develop extreme self-love because you see yourself through a mother's eyes.   It's addictive. It's absolutely addictive. But then the narcissist switches and says, okay, I've been mother to you long enough. Now I want you to be mother to me. I have mothered you.  So it's a dual mothership or dual maternal role situation. And in this sense, it's very regressive because if the narcissist plays a maternal role, it means you must play a child's role. You must infantilize yourself. You must regress.  Child in every sense, including vulnerable and helpless and dependent. So the narcissist offers you a fustian deal. He says, listen, I think you're perfect. I think you're amazing. And I want you to see yourself this way through my eyes.  I'm going to give you unconditional love. The only thing you have to do is you have to stop to exist as an adult. And you have to reemerge or resuscitate or revive as a child. Totally dependent on me, my extension. That's the only thing I'm asking of you, to suspend your animation. So how does one create a mind pivot? Because I know that you yourself, you're self-acclaimed narcissist. And yet at the same time you're doing all this work, that's promoting awareness around the disorder. So how does one create a mind pivot? Is it through recognizing? Is it through the recognition of how it actually processes through the mind, how it actually exists as a disorder? Or is it actually possible to create a mind pivot? Can you become, can you be a narcissist that becomes not a narcissist? You're talking about mind pivot with the narcissist or mind pivot in his victim? That's the one, the narcissist themselves through awareness, through self-recognition, through observing these states. No, it has zero impact on the narcissist. Narcissists cannot have insight. Insight requires a cognitive element and an emotional element. And narcissists have no access to any positive emotions, only to negative affectivity, only to negative emotions. So because they have no access to emotions, they cannot couple emotions with cognitions, with thoughts. So their awareness remains only called and cognitive, like reading a book or watching a movie.  So there's no way to transform a narcissist, a renderer narcissist, not a narcissist. Narcissist is the essence. Okay, and this is one effect the victims then, of course, because they find that mind-blowing, they find that hard to believe, yeah, that this state of that non-emotional state, that I suppose they think that their love can heal them or something. Is this something to that effect? Yes, I call it malignant optimism. Victims have this malignant optimism. It's grandiose, of course. There's an element of grandiosity in this. So their narcissism, the victim's narcissism, resonates with the narcissist's narcissism. That's why they bond. And so she says, I'll give him love, I'll give him acceptance, I'll give him the warmth he never had. He's a child.  I will hold him and embrace him and contain him and he will grow and he will heal, he will heal and so on. These are all utter, unmitigated narcissists, blood and ash. There's no way to transform the narcissist, meaningfully. Even my cold therapy, which is a treatment modality that I had developed with first-hand information, mind you, even that therapy, all it does is eliminates the grandiose aspect of narcissism, but not the rest. There's no way to touch narcissism because it is the core, it is the empty core. That's a black hole. So it's a hopeless quest to try to transform the narcissist. Now, with regards to victims, I think the best way to look at it is to consider victims as addicts. They had become addicted to the intoxicating sensation of seeing themselves idealized. So it's this laser focus on the victim at the initial stages of the shared fantasy. And then this photoshopped image of the victim, the narcissist provides the victim with access to this idealized image, what I call the wall of mirrors. The victim doesn't fall in love with the narcissist. It's not possible to fall in love with the narcissist.  How can you fall in love with them? You don't fall in love with any narcissist.  You fall in love with yourself. You fall in love with yourself through the eyes of the narcissist and then he becomes an indispensable venue or conduit. It's like if you want to watch television, you need to have a television set. So if you want to see yourself idealized, you can do it only through the narcissist.  Think of it as a drug addiction. He becomes your pusher. It sounds very like heroin. Yes, he is your pusher and you're addicted to this self-gazing, naval gazing and constant infatuation and limerence with yourself, with your idealized self. So this is why when you break up with the narcissist, you have not only a heartbreak, but you also have withdrawal symptoms akin to cold turkey because you no longer have access to this idealized image. You have been reduced again to your old pedestrian mundane self and that's a huge fall from grace. It's an expulsion from the garden of Eden. You're expelled. Yeah, when you're talking there, I feel like the story, the Greek classic of narcissists and echo and when you're talking, I can almost see the diminishment of a person's self through echo. She becomes diminished, more diminished, more diminished and there's that kind of feel to what you're talking about. But how do we help the victim? Is this going to be a repetitive cycle then, like addictions, like all addictions? Are victims going to keep rolling into different relationships with narcissists? I'm the messenger of the bringer of bad news always. First of all, it's my pleasure to discourage people and humiliate them, so I hold them in contempt. But jokes aside, the reality is this. Most victims of abuse and especially narcissistic abuse are likely, extremely likely actually to be revictimised multiple times and that is regardless of their level of awareness and knowledge, as you heard. Sam, so when we're talking about victimhood and I suppose this is, as you say, like victimhood is, it's a big deal now. There's a lot of economy around victimhood and it's something that's quite pervasive in society, as we discussed earlier. I'd like to know how to assist victims or in observing the red flags regarding narcissism. So what would a victim need to look out for if there is this repeat pattern of rolling into abuse or abusive relationships or narcissistic behaviour? Revictimisation happens for a reason. The narcissist caters to the psychological needs of the repeated victim. The narcissist provides what we call ego boundary functions. In other words, the narcissist allows the victim to regulate her internal environment, for example her moods, her emotions. And so the narcissist becomes an extension of the victim's mind and what we would call an external re-regulator. The victim becomes dependent on the narcissist or the abuser, not only narcissists. The victim becomes dependent on the narcissist for her day-to-day functioning and equilibrium and the homeostasis of her mind. Without the narcissist she becomes dysregulated, overwhelmed, she drowns, she's disoriented and she develops amnesia, deep personalisation, derealisation. In other words, she becomes dissociative. There are grave consequences to breaking up with the narcissist and there are even worse consequences for being alone because the typical victim of the narcissist has a very low tolerance for uncertainty, for loneliness, for emotionality and so on. So she crucially depends on other people, not necessarily only intimate partners, but for example family members. She's crucially dependent, end of story. And so I would reverse the current, the orthodox wisdom. The current wisdom propagated by numerous self-styled YouTube experts is that you have to look for red flags and warning signs when you meet someone. But I think you have to look to yourself for warning signs and red flags. You have to monitor your own reactions. You have to pay close attention and observe your moods or the lability of your moods.  Do you feel submerged, assimilated? Do you feel that you're merging and fusing with the other person? Do you feel that the other person is starting to have control over your moods, can make you feel bad, can make you feel good with a single word or a single gesture or a body language or a facial micro expression? Do you find yourself on the first date sort of deferring to his judgment and his decision-making? He decides where you go, he decides what you do. Do you find yourself walking on eggshells? Do you suddenly spectate? In other words, do you observe yourself from the outside and trying to conform to his expectations of behavior and proper conduct and his code of appropriate comport? So if you are beginning to mold yourself pretty consciously, if you're beginning to mold yourself, for example, you hesitate to be independent or to do anything autonomous or even to go to the loop on your own because you see that he's very jealous and so monitor his behavior, observe his behavior when it comes to people he perceives to be inferior to him, people he holds in contempt like waiters, cab drivers. And so is he being, does he put them down? Is he being contemptuous? Is he being, does he humiliate them? Does he rejoice and is cheered by pain that he causes others? Could be psychological pain of course, yes? So if he's this kind of a person, it's a warning sign. If he does not respect your boundaries, and this could be very, very small things, very, you know, things you tell him to not do and then he does them.  These are bridges of boundaries. He does not regard you as a separate person, as a separate entity, he's taking over you, he's assimilating you, his body's snatching and mind's snatching you. Now all these things, all of them without a single exception, happened within the first hour of the first date. So why do people deny, why do people ignore these warning signs and flags? Because might it be because there's there's a history of that, you know, like some a lot of a lot of people who engage with narcissistic relationships have narcissistic parents, right? They've grown up with that level of complacency. They've grown up with that level of non identity or floater identity where they just dovetail. Might that have a lot to do with it? I know I'm intervening there now, but you know, they perfectly respect your boundaries. Yeah, desensitization is the clinical term for what you're describing. They're desensitized to these behaviors. They don't regard them as misbehaviors.  So, yes, that's one aspect, but I think even much more so is what we call the loneliness gap. People have been exposed to inordinate amounts of loneliness, extended periods, protracted periods of time, where they had been utterly lonely, with the exception of a pet and Netflix. And people are not built to survive this way. And so they, they pounce, they pounce on the first opportunity to not be alone. This would explain, for example, the rising preponderance of casual sex.   It's very bad sex. But it's not about sex. It's about having a warm body next to you. It's about a dose of affection. It's about being seen if even casually. It's about fake intimacy, if only for a night. Casual sex is an antidote to loneliness, short doses of antidote to loneliness. So people are terrified of loneliness. And when they see a possibility, however remote and however unappetizing, to not be alone, they pounce on it. And they deny, ignore, reframe, lie to themselves, self-deceive, create narratives, become delusional and engage in fantasies, anything. Just to not go back to your pet and Netflix is the only social option. Wow. So it's kind of like we're filling a void. So there is this, in essence, it's filling a void. But what is the worst thing that could happen if we face that void? What's the worst thing that could happen to face it, to become the void, to embody that space? Like what is the worst thing that could happen? The flip side of this question is what is the purpose or what are the functions of socializing with other people? And the most important function by far is self-calibration. We use other people to gain, to be seen. And through the gaze of other people, we gauge, we evaluate and appraise ourselves, our appearance, our behavior, our beliefs and norms, our goals. So other people calibrate us, they center us and they ground us. When we have very low periods, and some people go for decades without seeing other people, I mean, I'm not talking about the pizza delivery guy, without having any meaningful relationship. And even a one-night stand is a meaningful relationship. You can't believe the hype that it's meaningless and emotionless. There are emotions there and it's fraught with meaning. It's fleeting, it's ephemeral, but it's meaningful and it's emotionful. But many, many people go many years and decades without even a one-night stand, nothing, no contact. So they become dysregulated. Even healthy people become dysregulated because we derive many regulatory functions from the outside, from other people. So they become less centered, less boundaryed, less sure of themselves. They begin to doubt themselves. They become aggressive, but because they don't have to, they become aggressive because they are sad and frustrated. But because they can't take out the aggression on anyone, there's nobody there. They take it out on themselves and this is what we call depression. So they develop depression.  It's much, much worse than Russian religion.  They go insane. When we isolate prisoners, when we put prisoners in isolation, which is a cruel and unusual punishment in many jurisdictions, it's forbidden in many jurisdictions, they go crazy. They go technically crazy. Now 45% of our adult population live in isolation, especially after the pandemic. The last remaining thread, the last remaining of opportunity for human contact was the workplace. But people now work from home. They don't see anyone to a three dimensional. They don't smell anyone. They don't taste anyone. They don't enter, they don't penetrate anyone. They're totally atomized, they float in space, and they're unable to gain bearings, they can't regain their bearings. People serve, other people serve as a set of coordinates. They allow us to locate ourselves within the map, within the map of the world. This is called the theory of a working model, an internal working model. That's a clinical term. So we develop a theory of mind and a theory of the world, but we can't do this without other people. There's no such thing as individual. It's a myth. It's a nonsensical myth that took, led psychology astray. There's no such thing as individual. An individual is the intersection of multiple relationships. It's like a Venn diagram. You have these two circles and the intersection of these two circles is you. So it's relational. And in the absence of relationships, there's no you. You lose your functioning ego and you become a narcissist because one of the best definitions of narcissism is someone who has no functioning ego. He is no functioning self. Ironically, narcissists are selfless. They don't have a self. And because they don't have a self, they take yourself. They borrow yourself. They ask you to lend them your selfhood because they don't have one. And so they sort of garner or collect narcissistic supply and then they construct these kaleidoscopic hive minds, which is the phone cell. And so if you stay alone for a long period of time, you end up being narcissistic and psychopathic. Simple. Okay. So basically you're saying that humans need to be living in communities that we're community based and that I suppose this is a function of being a mammal and having by nature mammals or community beings. And our world is devoid at the present of this contact. And I suppose, as you talked about earlier, the family structure as well. People are more younger. People are living at home with their parents. So there's kind of like an infantilizing process taking place of society where you know, people are becoming more codependent, but in a negative way, like from what I've heard you speak of. So what is the solution? How do we change? How do we move the cogs in another direction? How do we create awareness? How do we create change? What is the life solution? What is available to us? The very question is imbued with the myths of Western society. Because the number one myth of Western society and the most pernicious one, the most dangerous one and the myth that had led in my view to all the to the panoply of ills that we are facing anywhere for anything from climate change to gender conflict or gender vertigo is the myth that there is a solution for everything, that there is always hope. There are numerous problems which cannot be solved ever. They have no solution and there are numerous situations with absolutely no hope. This is one of them. We are drifting apart from each other because we had constructed the world where loneliness pays. It has a premium. In 1980, in 1980, twice as many people were in committed relationships and the rate of marriage was double 50% higher. No, let me think. Yeah, 50% higher what it is today. Additionally, a typical person had 10 close friends. The picture today is this. 45% are lifelong singles, 31% are lifelong singles, another 15% are singles at the moment. People have a single close friend, not 10, one, it's a 90% drop. Dating has collapsed by 60% within a decade. Who cups have collapsed by 25% within the last five years? Even though we have dating apps and everything, people don't hook up anymore even. So something of this magnitude that happens within a decade because this or everything I've just described happened within the last 40, 30 years and most of it happened within the last decade. Something of this magnitude is what we call a positive adaptation. In other words, the world had changed and we needed to change ourselves really, really fast if we had to survive, if we wish to survive. As if all of us wish to survive, that's precisely what we did. We had transformed ourselves really, really, really fast because the changes were ominous and life-threatening. Now why would we want to be lonely? Excuse me, why would we want to be alone? And first of all, this distinction is very important. Alone is a state of being. Lonely is a state of mind. It's a reaction to being alone. And it's a socially dictated reaction, what we call a sublimated reaction, socially acceptable reaction. Why would we want this? Why would we seek it? Well first of all, because we can. Technology had empowered us to the point that we are right now absolutely 100% self-sufficient. What you're doing right now with me would have taken an investment of $50,000 in 1980 and half a million dollars in 1960. You're doing it with me and I'd be shocked if it cost us more than a single dollar. So technology had empowered us to the point that we had become godlike. We can publish books. We can make movies. We can do anything from home. We are utterly self-sufficient. We don't need other people. There's no reason to pay the premium of interacting with other people because other people take energy. Other people require compromises. Other people create friction and conflict. These are the costs of interacting with other people. We don't want to pay this cost anymore because we don't have to. We can survive perfectly well on our own. The mental correlate of this is going crazy, but going crazy for example via substance abuse and so on. Going crazy is such an incremental process, such a glacial process that we don't notice it.  So while the benefits of being lonely are immediately discernible because you can do anything you want with anyone you want or with no one and you can entertain yourself and you can create and you can work and you can make money and you can travel and you can go out with friends, there are numerous benefits to being alone. The costs of being alone are very long in coming and utterly not discernible. So we don't realize it before it's too late and then when it's too late we desperately thrash about looking for intimate partners and we can't find them. I will describe to you, I'll tell you just about one mismatch. Men look to settle down between the ages of 25 and 27. That is the apex of men's desire to settle down, believe it or not. Women look to settle down between the ages of 32 and 35. That is the apex of women's wish to settle down, probably the biological clock and whatever, they want children or whatever the reason may be. There's a total mismatch because by the age of 32 the majority of men lose their will and wish to settle down and by the age of 42 97% of men do not want to settle down vehemently do not want to settle down. So there's an enormous mismatch when men want to settle down, women don't want to settle down because they're pursuing studies and a career and they want to travel and they want to go out with friends and they want to f-around. When women want to settle down there are no men left, there are no men who are interested. So by the time you're 35 your chances to get married are substantially or even hitched, not married. Chances of finding a partner are substantially diminished by the time you're 40. So what you're describing there is that our lifestyle choices have basically affected our biology and have impacted on our current world, its reproduction levels, its family structures and I suppose since you spoke about it earlier our inability to share. And yet is there not a drive in every human to do better, to be better, to be a better human? Like are we not impacted by our choices, by this loneliness you speak of? Is there enough this also like you know okay there's hope is the delusion of the ego but is there not also a drive to better oneself or to change fundamentally? People don't consider intimate relationships as bettering themselves, they consider intimate relationships as serious threats. When they are in college having an intimate relationship is a death sentence, later when they are developing their careers falling in love is a death sentence and then when they do look for an intimate partner they don't have the skills, intimacy skills, relationship skills because they spend 15 years, 15 years having sex with total strangers in a totally intoxicated state, inebriated sex is not a good preparation for intimacy and a long-term relationship trust me. So people regard intimacy falling in love they call it catching feelings, the phrase for falling in love is catching feelings, catching feelings sounds like a virus, sounds like a serious disease like COVID-19. So people begin to regard other people as a threat, as a menace because they can fall in love with other people, they don't want to fall in love. Today Hannah Rossin to the feminist she wrote that today to fall in love is like to be a teen a pregnant teen in the 70s, it's as bad. Then she said the best thing that had ever happened to women is the hookup culture because it allows them to satisfy their sexual desires without paying any emotional price or career price. When young people, young I mean under age 35 I asked what do you value more career money or a committed relationship, 70% say career and money, only 30% say a committed relationship. So the presumption that not being alone, having an intimate partner, being in a relationship, loving someone are hopefully in a form of personal growth development and betterment these are 1980s, 1990s sentiment, it is so passe. Today the opposite is true, to better oneself, one absolutely needs to remain alone. One absolutely needs to remain single, it's the only hope of progress making more money, bettering oneself and so on. Now the statistics define this it's a counterfactual belief because the statistics show that married couples make a hell of a lot more money than singles and that married couples are a lot healthier than singles and live much longer than singles, married by the way, not cohabiting, not committed. So it's not true that cohabitation and committed relationship but not marriage is the same like marriage, it's not as far as the effects. So it's good to be married, shockingly, even a bad abusive marriage has greater benefits than living alone in terms of health, income and so on. These are the statistics, unpalatable maybe, but I'm a scientist, I'm data-driven. But people don't want to hear that because they are not willing to pay the price of being with someone. There's huge costs involved in accommodating yourself, in compromising, in deferring and in delaying gratification, there are huge costs involved and people have not matured, they haven't grown up, they are incapable of everything that adults are supposed to do. And then when you're 35 and you go out to the marketplace, you've left finally the parental nest and you go out to the marketplace, you're ill-equipped, there are dating assignments in universities in the United States as part of classes, you get credits, they teach you how to date and they teach you how to date at age 24, 25 and 27 because you don't have a clue how to date and you get credits for that.  That's kind of like a progression there, it's kind of like teaching your nation nationalism and how to be nationalistic while teaching your nation how to mate, you know? Kind of, they are so clueless, so absolutely clueless when it comes to interacting and so gender roles are dead, which is not entirely a bad thing because a big part of gender roles was about dominating women, subjugating women and abusing women, of course. So what the family is called the patriarchy. So gender roles are dead but instead what had emerged is not new gender roles, which would have been very welcome, but a uni gender world where there are only men with some of them with penises, some of them with vaginas, as we have today. Women, according to studies by Lisa Wade and the college, the famous college survey and numerous other studies, women are describing today themselves in totally masculine terms. Seven out of eight adjectives chosen by women to describe themselves are stereotypical chauvinistic masculine terms. Not merely masculine, but chauvinistic masculine.  Can you give me an example of that, how that would show up or manifest? Like for me when you're talking, I mean, I'm trying to use this as a reference point, I go to a certain kind of new culture of this divine feminine rising, which is this whole culture of women taking on the patriarchy, women seeking revenge on the patriarchy. By the way, for me, being a woman is just that. It's just about I'm born this way, but it doesn't really affect, you know, how I view the world or how I view men even. It's just I'm born this way. But for me, more importantly, it's about being a human being.  And I think that that's a better approach from my point of view. What do you think, like, is the best approach to gender? And do you feel that if men and women could meet in this regard, do you feel that men have been demasculinised? Have men been, has their male been taken from them in some way from this attitude that women have towards men? No, men have not been demasculated. Our studies don't show this. Men still describe men still describe themselves largely stereotypically as they used to do in the 70s and 80s and 90s. So there's been no change, no shift. This is called in in the literature the Stormed Revolution. The Stormed Revolution because only half of the revolution took place. Women became more masculine, but men did not become more feminine. So we ended up having only men. Men with two different sets of genitalia. Now, I think we should make a distinction between gender roles, social scripts and sexual scripts. Gender roles are dictated by society and culture largely. We have situations even in primitive societies, so-called primitive society, like for example, in big parts of Africa, where I'd lived for four years, in northern Albania, which is a seriously backward country. So where women take on classical male gender roles and are treated as male, they're allowed, for example, to sit with men in a cafe and smoke.  In big parts of Asia, big parts of Africa, some parts of the Middle East, big parts of the Balkans and Eastern Europe and so on, women would find the idea that they cannot be men very funny. They wouldn't understand exactly what you're talking about because it's very fluid. Gender fluidity did not start in the United States. It's been around for thousands of years in the so-called more primitive parts of the world. So I'm not talking about classical gender roles, but there is no question that we have a difference in biological equipment. There is also no question, which I'm saying as a medical doctor, that we have massive differences in physiology, hormones, and brain activity, operation of the brain and so on. There are differences. There are hundreds of substantial differences between men and women, biologically grounded. Now this should be, should translate into new gender roles. The new gender roles should take into account social scripts. So for example, the current social script should include equality, total equality, and total equity. No glass ceilings, total wage equality, I mean everything. No question about this. So the social script had adopted and had changed, at least in theory. Sexual scripts were annihilated, so we don't have any more, any sexual scripts left. And the outcome is a radicalization among men. Some of them gravitate towards the most extreme and pernicious forms of toxic masculinity. And the double standard is more entrenched than ever among these men. So this is one group and the other group are lost, dumbfounded, shocked by the alacrity of the transition, by the speed with which it had happened. And they don't know what to do, because no one tells them what to do. Everything is negotiated one-on-one. It's not necessarily a good thing to negotiate everything from scratch one-on-one, not necessarily a good thing.  Then people derive, I mean, men gravitate, I mean, look to pornography to tell them what to do, because they're lost. And so we have this radicalization of masculinity on the one hand. And on the other hand, women, definitely as a group, I mean, the statistics are absolutely unequivocal. Women as a group had taken on a stereotypical, chauvinistic, bullying, narcissistic, and psychopathic stereotype of a man that tried to emulate this, that tried to become this kind of man, which, by the way, the vast majority of men holding contempt and disgust, we had rejected this kind of men. We think they're horrible and obnoxious, yet they had become the role models of the modern woman. So we find heightened levels of dominance and aggression among modern women. We find reduced, severely reduced, or suppressed, or denied, emotionality and empathy. There's a huge decline in empathy. There is a doubling of narcissistic personality disorder, diagnosis among women, and a quadrupling of psychopathy diagnosis among women, and so on and so forth. So it's very sad because what we should have done, we should have created new gender roles founded on new sexual scripts, social scripts, I'm sorry. And these two put together should have created a new sexual script. How should you behave with each other? Men with women and women with men. So maybe the new sexual script, for example, would imply equality in initiating sex. Nothing wrong with that. Maybe it would have implied, I don't know what it would have implied because we don't have a sexual script. And so today, if you have casual sex, you have a huge chance of being sexually assaulted. 27% actually.   I mean, it's just horrible because they don't know any better. There's no sexual script. I mean, someone in the 1950s knew what he had to do. He had to invite the girl and then he had to take her to a diner and then they had to go to a movie and then he could try to grope her in his car.  We don't have this today. And everyone is drifting and lost, women included, but the drifting, that's why women participate in hookup culture. Hookup culture is the epitome of toxic masculinity. Absolutely, the reification of toxic masculinity.   End of story, that's the hookup culture. And women participate willingly in the hookup culture. Why? Because they want to be men, liberated, emancipated, empowered. They don't understand. They're buying into the male chauvinistic script. So what you're saying is it's a concept. It's a conceptual space. It's not an actual active space of feminine empowerment or female empowerment. But I suppose that just from listening to you today, the listeners will, I mean, I myself have found this to be very revelatory. And I suppose the statistics and the facts speak for themselves. They're very truthful and in a way highlighting error and highlighting truth. And this truth, hopefully, will reverberate and touch and contact people's lives and perhaps wake people up. And I think you yourself are very, in how you speak of like society and of women and equality for both men and women. I think that's very honourable. And I just wanted to say thank you so much for giving us your time with the FlowGrow experience and sharing your wisdom and your knowledge and your mind. And thank you very much. It was an honour speaking to you. Thank you for having me and it was a pleasure. Thank you. Bye bye.


So, now we will move to the synthesis of another important vitamin called a biotin. This biotin plays a very, very important role in physiological process like gluconeogenesis and fatty acid biosynthesis. So, obviously a lot of interest was there in early 60s, 70s, 80s to synthesize this biotin. So, today we will talk about one total synthesis of biotin and when you look at this molecule immediately you can see that there are three contiguous stereocenters. So, 1, 2, 3. These three are chiral centers and they are contiguous and there is one tetrahedral thiophilin ring. You can see completely reduced thiophilin ring and there is a 5-carbon side chain having carboxylic group at the terminal end. Then you also have a cyclic urea, you have a cyclic urea. Then if you look at the whole biotin, the difficult part is the carboxylic acid and these three chiral centers. So, you are going to introduce these three chiral centers stereoselectively so that biotin can be made in naturally occurring form. So, the first synthesis was reported by Roche group and here they used a very interesting intramolecular 3 plus 2 cycloaddition of a nitrone and an alkene. They started with naturally occurring amino acid, cysteine, actually they used a dimer of cysteine, cysteine and they tried this intramolecular 3 plus 2 cycloaddition reaction. So, what is this 3 plus 2 cycloaddition between nitrone and alkene? This nitrone, when you look at nitrone, nitrone is nothing but if you have an emine and if the nitrogen is oxidized, okay, the oxide of nitrogen, okay normally you know we talk about n-oxide, n-methylmorphylene, n-oxide, tri-methyl amine, n-oxide. So, here nitrogen of emine if it is oxidized then that is called nitrone and this nitrone if you look at carefully it has one electron deficient end and one electron rich end. So, it is a distributed over 3 atoms, okay. So, when you do a 1, 3 dipolar cycloaddition with an alkene and if the alkene is electron rich then this is what the stereochemistry of the product which you get, okay. So, obviously this is electron rich and this is electron deficient. So, you can see the bond forming between these 2 carbon atoms. Likewise, when you use electron deficient dipolar of ions, okay then what will happen? This is electron rich and this is electron deficient. So, this is where the bond will form and the stereochemistry will be reversed, okay. So, this nitrone alkene cycloaddition has been successfully used to make 5-hombard ring which you can call it as exoxazolidine, okay. But contrary to 4 plus 2 cycloaddition that is our Diels-Ald reaction. Here the secondary orbital interaction is not there or it is very, very minimal. As you know when you talk about 4 plus 2 cycloaddition or Diels-Ald reaction the secondary orbital interaction is important for getting endoisomer as the major product. Since this nitrone alkene cycloaddition that is 3 plus 2 cycloaddition does not or involve very little amount of secondary orbital interaction you do not have to get only the endo product as the major product. In fact, you get exo product as the major product and the formation of exo or endo is mainly controlled by your substrate or if you are using a catalyst. Only it gives the exo product and if you take this cyclic nitrone and treat with dipolar file like acrylonitrile then you get this as the major product this is nothing but exo product. And here this is a bottom phase approach of dipolar file that means you have the nitrone like this and your dipolar file attacks from the bottom, okay to give this as the major product. And there are several intra-molecular 1-3 dipolar cycloaddition between a nitrone and alkene present in the same substrate is reported for example you can see this molecule this can be redrawn like this. Now this O- will attack here and this double bond will attack and the positive charge on the nitrogen will be neutralized to get this tricyclic ring, okay. And this is a isoxazolidine and this endo bond can be easily cleaved with zinc and you can also cleave it with hydrogenation condition you can also cleave it with LAH. So that will give you amino alcohol and this is another example this is intermolecular and still you can see there are three chiral centers, okay. Three chiral centers one can fix during this 1-3 dipolar cycloaddition depending on the nature of your substrate, okay. Now again if you cleave this eno bond, okay so that will give you this amino alcohol and when you use LAH not only the eno bond gets cleaved but also the ester so you get two hydroxyl group one primary and the other secondary in addition you get a secondary amino group, okay. And this also can be rewritten like this. So I also will show you another example of intramolecular nitron-alkene cycloaddition because this is important so that you will understand the 1-3 dipolar cycloaddition which is involved in the synthesis of biotene as the key step, okay. So this starting material is called citronellol commercially available this all treatment with methyl hydroxyl amine it forms a nitrone and the nitrone undergoes 1-3 dipolar cycloaddition and it goes via this nitro you can see this can be drawn like this a chair like transient state you can write and followed by formation of this 5-ohm buttery. Again you can cleave this you will get corresponding amino alcohol. Now let us see how this biotene was synthesized what was the retro synthesis by Roche group. So what they did was they introduced an extra hydroxyl group in biotene that was a first retro synthetic you should not call it as disconnection but as introduction of additional functional group required for better disconnection. So why they introduced a hydroxyl group because they wanted to use a 1-3 dipolar cycloaddition as I said when you do a 1-3 dipolar cycloaddition between nitrone and alkene you get isoxazole and if you cleave the NO bond you get amine and alcohol. So that is why they deliberately put this hydroxyl group so that this hydroxyl group along with this nitrogen you know it can form during the dipolar cycloaddition. So then they said if you can look at this complex structure okay so this is formed if you cleave this NO bond if you cleave this NO bond you will get this okay. But this isoxazole can be obtained from the nitrone this nitrone and the double bond okay. Now this O- will attack here and the double bond will attack so it will form a 5M buttery and this nitrone I leave it for sometime so that you can visualize any of you can discuss more when we talk about the total synthesis. Now you just see can be obtained from this particular compound and which can be made from commercially available amino acid called cysteine okay and from cysteine you can acylate with this carboxylic acid. So basically what you are doing is you are going to start with L-cysteine methyl ester and this acid chloride which you can make it in 3 to 4 steps and it is a known compound okay. So now let us see how the Roche group synthesized biotein so they started with L-cysteine methyl ester then acylated to get this compound okay. Then the this is a dimer you should know that this is a dimer S, S and the dimer. So you can cleave the SS bond with metal. So for example if you use zinc and acetic acid that SS bond will cleave and then you will get corresponding SH. So the SH spontaneously will add to the triple bond SH will add to the triple bond and you will get in thioether okay. Then what you do you have to reduce the ester to aldehyde because aldehyde is required for making nitro okay. So you reduce the ester to aldehyde in one step with di-ball then you treat with benzyl hydroxyl amine okay. So when you treat with benzyl hydroxyl amine this aldehyde will form a nitrone okay. You can see the nitrone now. Now once you have this nitrone this undergoes an intramolecular 1, 3 dipolar cycloaddition that will give you the corresponding high succes already okay. So I leave it for a few minutes so that you know you can understand how this 5 membered ring is formed. Already I put the arrows properly so it will be easy to understand. Nevertheless from the stereochemical point of view I leave it for 30 seconds so that you can understand. Once you get this isoxalidine obviously the next step is the cleavage of the ennobar okay.  So you have to protect the amine once again. So that was done with chloromethyl formate in the presence of base like sodium carbonate. So now the amine is fully protected. Then you can hydrolyze this amide okay. The hydrolysis of this amide was done with barium hydroxide in reflecting dioxin water to give the corresponding carboxylic acid and amine okay the amide was cleaved. Once this amino acid is formed then what happens the lone pair on the amine attacks this carbomate then OME comes out that leads to the formation of this urea derivative cyclic urea derivative okay. This NH2 attacks the carbomate carbonyl OME comes out and you get the corresponding the urea derivative cyclic urea derivative. Can you redraw this as this bicyclic compound? You can see first the cyclic urea yes you have done the cyclic urea. Then attach this tetrahedrothiophen okay and you can see both ring junction hydrogen or beta so you have written beta and next you have the 5 carbon side chain that 5 carbon side chain with a hydroxyl and carboxylic acid okay. Same thing if you rotate it by 180 degree rotate it by 180 degree you will get this rotate it exactly by 180 degree. So the thiophene will come down and the urea the tetrahedrothiophene will come down the cyclic urea will go away. So if you look at this structure now what is missing or what you do not want. So there are two things you do not want one you do not want this hydroxyl group two you do not want this benzyl group. So if you can remove the hydroxyl and benzyl group that will lead to the formation of biotech okay. So how it was done? You first try to remove the hydroxyl group when you treat with thionyl chloride first the carboxylic acid will become acid chloride okay. Then that hydroxyl also will attack the thionyl chloride and it forms the half thionoyster okay. So this you have a lone pair on the sulphur of tetrahedrothiophene that will intramolecularly attack and your OSOCl will go out. So that will form a three-membered ring with sulphur having a positive charge. Now what will happen? The chloride which comes out okay. So now if you see here the SO2 will come out which is a neutral molecule the chloride which comes out again it will attack. So it is a double SN2 reaction on that carbon so you get again the beta chloride okay. Now the chloride can be removed with sodium borohydride and HPR water not only hydrolyses the ester but also removes the benzyl group to give biotech okay. So to summarize this in 1982 Roche group discussed the first amylocelective totals in this is a biotech and they use the amino acid L-cysteine which is a dimer of L-cysteine and they used an intramolecular nitrone olefin cyclo addition to fix the stereochemistry of nitrogen and the hydroxyl group. The hydroxyl group as you know it has to be removed but nevertheless to fix the stereochemistry of CN bond they use the intramolecular nitrone olefin cyclo addition reaction overall this synthesis was done in 11 longest linear steps and the yield was impressive of about 8%. Even though the molecule looks small overall yield of 8% is considered decent one for such molecules okay. So now we will move to the synthesis of other natural products having 5-unbuttering. So we have been discussing about total synthesis of penicillin type antibiotics and we will continue our discussion on one more natural product close to this. So that natural product is called Lacta-cysteine this was isolated in 1991 by Omura and his group and the structure was elicited by the various spectroscopy techniques particularly the X-ray was very helpful and if you look at this molecule closely it has 2 amino acids so 1, 1 here and then second one is here. So 2 amino acids and then N-acetyl-cysteine is also part of this amic acid derivative. The first total synthesis of Lacta-cysteine was reported by E.J. Coray a year after it was isolated and his synthesis involved many key reactions which I will discuss when I talk about the retrosynthesis as well as his synthesis. The first obvious disconnection of Coray's retrosynthesis of Lacta-cysteine was to cleave this part that actually simplifies the natural product so into 2 fragments. So now this carboxylic acid if you look at carefully so you have a carboxylic acid here and then your Lactam and of course you have 2 hydroxyl groups here there are 4 functional groups a carboxylic acid a 5 membered Lactam and 2 hydroxyl groups both are secondary. So if you look at this how he has made this compound from this particular compound you can see you have the hydroxyl group is still intact the second hydroxyl group is still intact and this one that is CH2O TBS. So that will form carboxylic acid that will become carboxylic acid is a latent functional group transformation then if you cleave this if you remove this CH2 then this NH can cyclize with this this N can cyclize with this that will form the 5 membered Lactam. Now let us see how he made this precursor. So this precursor he made it from here so just you have to generate anion and then quench with an electrophile and this is nothing but you know if you have to make this you can make it from another commercially available amino acid called serine. Serine is nothing but so this is serine so from serine one can make this in 2 steps so that was a commercially available starting material also. You take this compound and treat with LDA so LDA generates anion here and quench with isobuteroid. So when you quench with isobuteroid now you can see he has introduced one more chiral center okay already there was one chiral center here second chiral center here so he introduced the third chiral center which is very very important. Now you treat with trifluoroacetic acid so the trifluoroacetic acid removes this protecting group so that gives you the corresponding N benzylated amine then the CH2 OH so you remove that and then you get the amino alcohol so that was redrawn like this okay leave it for few seconds so that you know you should be able to understand the CH2 OH is beta so it is beta and then NH benzyl is there. Take this compound and then treat with TBS chloride so TBDMS chloride you can protect the primary alcohol okay you protect the primary alcohol as TBS ether then treat with toluene sulfonic acid and formaldehyde this is NH and this is OH okay you can see NH OH and if these two are protected with formaldehyde again you will get a five umber ring is not it again you will get a five umber ring so that is what happened okay you can see you protect this amino alcohol then the ester you could reduce with lithium borohydrate to get the primary alcohol then sworn oxidation will oxidize the primary alcohol to corresponding aldehyde. So this is the key fragment which you could make in few steps starting from commercially available amino acid called serine then you take this 2-dimethylphenol 2-6 dimethylphenol and then treat with propionic anhydride you get the corresponding ester that compound upon treatment with LDA you generate anion you generate anion then quench with this aldehyde okay it is an aldol reaction basically an aldol reaction and you get this aldol okay. Now from here how he goes to this one carefully observe okay you have the aldol next you have to remove this CH2 you have to remove this CH2 at the same time you also you have to remove the n-benzyle so if first if you do hydrogenalysis what will happen the benzyl group will be cleaved the benzyl group will be cleaved so that automatically once it cleaves it will attack this carbonyl group and you have a good living group 2-6-dimethylphenol phenol is a good living group okay and that will give this interpretation okay. So it is easy to visualize because I have to I have rotated 180 degree so that is why I am just leaving it for sometime from the natural product side you know you have to write like this so that is why I have rotated 180 degree I will leave it for sometime okay this portion this portion has come to the right side okay that is why everything is exactly opposite TBS was removed with HF then swan oxidation gives the corresponding aldehyde okay swan oxidation gives the corresponding aldehyde next step is oxidation of the aldehyde to corresponding carboxylic acid following Pinnick's protocol then treat with 1-3 propane diethyl what will happen when you treat with 1-3 propane diethyl 1-3 propane diethyl in the presence of HCl this CH2 that is formaldehyde is not it that CH2 when it is cleaved under acidic condition it is formaldehyde that formaldehyde will be protected with this 1-3 diethyl and leaving out your amino alcohol basically you are cleaving that protecting group with 1-3 propane diethyl with HCl okay. So now as I said there are 4 chiral centers in lactose cysteine lactose cysteine 1, 2, 4 all 4 are done okay now we have to attach the thiol side chain so that you can do from cysteine okay the cysteine N is protected as acetate and then the carboxylic acid is protected as allyl ester okay. So now you couple this with carboxylic acid so you get the corresponding thiol ester okay. So what is left you have to remove the allyl group okay so how do you remove allyl group palladium catalyst so if you treat with tetraxyl palladium in the presence of armic acid so you get lactose cysteine so basically this was a very elegant total synthesis starting from commercially available amino acid called serine. See there are 2 amino acids he used one serine another one is cysteine okay other chiral centers he used based on these 2 amino acids. So this was the first total synthesis reported by E.J. Coray and the key reactions are aldol reaction mainly aldol reaction and then 2 types of protections he carried out so that was important while carrying out the next aldol reaction. Overall this synthesis was accomplished in 14 steps and he has to use few protecting groups say when you use once protection you are adding 2 reactions if you use more protecting groups accordingly you have to multiply by 2 because 1 step is required for introduction and 1 step is required for removal. So that is how the number of steps has increased to 14 and with the overall yield of 6 percent then the second total synthesis was reported by Baldwin in 1994 2 years after E.J. Coray reported the total synthesis and here again he started with another commercially available amino acid glutamate and let us see how he made this. His retrosynthesis again as you know the cleavage of CS bond is the first thing then he wanted to introduce the hydroxyl group here using a dihydroxylation method if you have a double bond then you can do dihydroxylation and then selectively cleave one of the hydroxyl group okay. So he wanted to do that and then this chiral center he wanted to introduce using aldol reaction okay. So that aldol reaction will give this compound and this can be obtained from amino acid for glutamic acid okay. Now let us see how he started and then how he got the synthesis of lactocysteine. So glutamic acid pyroglutamic acid and treatment with thionyl chloride ethanol you convert that into ester ethyl ester and ethyl ester can be selectively reduced in the presence of lactam using lithium borohydride to get the corresponding primary alcohol. This upon treatment with the para toluene salphonic acid and benzole guide you get the bicyclic ring and one more chiral center is fixed okay. With this one can generate anion here and quench with methyl iodide to get the methyl group then you introduce a phenyl salenate group. Introduce a phenyl salenate group here by treating with LDA and quenching with phenyl salenate bromide followed by treatment with ozanalysis you introduce or you oxidize the phenyl salenate group to phenyl salenate oxide followed by elimination to get that double bond. And as I mentioned once you have the double bond the next step is the dihydroxylation. So the dihydroxylation before doing the dihydroxylation he wanted to do an aldol at this carbon. So at this carbon means you know alpha beta gamma carbon because if he does dihydroxylation at the double bond then the gamma position it will be difficult to oscillate or do aldol reaction. So what he did he wanted to do the aldol reaction first. So he treated with the TBS triflate and then 2,6-lutidine. So that form the dienolate the dienolate was quenched to form the corresponding TBS ether. So this is almost now we can see it is like pyrrole ring is not it that pyrrole. Now if you treat with isoputroldehyde in the presence of Luisa I said like tin tetrachloride the aldol reaction takes place at gamma carbon. So that is how we can see this stereocenter was fixed. So now you need one more hydroxyl group at this beta carbon. Again the free hydroxyl was protected followed by aspen tetroxide treatment you got the diol. Now you have a tertiary alcohol and secondary alcohol. The secondary alcohol should be intact but tertiary alcohol should not be. So what he did cleverly he treated with CDI that is carbonyl diumetazole. So that reacted with tertiary alcohol to form the corresponding thio derivative. So now this type of derivatives are known to undergo deoxygenation. If you take this compound and treat with tributyltrinhydrate in the presence of AABN. So that will undergo deoxygenation. So only problem is this methyl group that chiral center is not one isomer. Nevertheless you treat with sodium hydroxide. So sodium hydroxide will hydrolyze the acetate as well as it will epimerize this. Sodium hydroxide will hydrolyze the acetate as well as it will epimerize the carbon adjacent to the carbonyl group. Done then this protecting group can be easily cleaved by hydrogenalysis. So you get a free amino alcohol. You have come up to very, very key intermediate now. How many chiral centers are fixed? Four chiral centers are fixed starting with one chiral center of pyroclutamide. Then protect the primary alcohol as T acetyl and secondary alcohol as acetate. Then remove the TS with 40% HF to get the primary alcohol. The primary alcohol what you want in lactocysteine is carboxylic acid. So in one part you can do with the Jones oxidation without touching the acetate, without touching the chiral center the primary alcohol can be oxidized to carboxylic acid in 15 to 30 minutes. Once you have the carboxylic acid then the acetate group can be cleaved with sodium hydroxide solution. Now you can see all the four chiral centers. All the four chiral centers are fixed. So what E has to do? E has to couple this carboxylic acid with a thiol and that thiol should be derived from cysteamine. So it took cysteamine then NH was protected as acetate and then carboxylic acid was protected as allene ester. Then this thiol can undergo coupling with carboxylic acid. Yes it went and it formed a corresponding thiol ester and what is required for the total synthesis of lactocysteine is to remove the allene group. So the allene group can be easily removed with tetracase triphenolposterene palladium and the formic acid and triethylamine lead to lactocysteine. So this is one of the simple and straightforward total synthesis of lactocysteine starting from pyroglutamate and it was also reported 3 years after the isolation of lactocysteine and the key reactions involved in the synthesis of lactocysteine by Balvin are stereoselective aldol reaction. If you look at the siloxipyrrol the aldol reaction took place at the gamma position. Gamma position that is the first key reaction where the quaternary center was incorporated with the chiral center. Then the this side aldol reaction and finally attachment of the cysteine. Overall this sequence took about 20 steps slightly longer than what Coray has reported. Nevertheless the starting material is commercially available that makes huge difference and it is not expensive and the overall yield compared to Coray's. Coray's was 6% and this is about 4.27%. Okay.  So we will move to the next natural products having 6-umbered as the core structure. Thank you.


When the narcissist is forced to accept the feat Narcissists are very sick twisted people They do some horrific things to their victims They will abuse you for years and never get tired of it because it fuels them It regulates their emotions It distracts them from their own miserable lives they will say horrible things about you They will physically abuse you They will sexually abuse you They will deliberately try to drive you insane They will minimise your accomplishments They will sabotage your success And if despite all of the abuse You're still able to function like a normal person They will smear your name They will change other people's perceptions of you But when they do that It should reveal to you that you are very strong The smear campaign is their last resort It is their last attempt at keeping you under their control They would rather continue with the abuse It's much easier for them to do that But if the abuse isn't strong enough to overpower you They're left with no choice If they continue against yourself They will turn the world against you So that despite all of the abuse you had endured You are still being punished Because now you can't live a normal life But unknowingly to the narcissist They've actually handed you the keys to what makes them tick They've revealed to you everything that is important to them Everything that they are envious and jealous of Which is the very thing that will help you to defeat them Narcissists are only concerned with superficial things So if you want to defeat the narcissist You need to work on yourself Go to the gym And become physically healthy Eat better foods Drink more water Start your own business and make lots of money Buy a big house Buy a luxury car Date a model It may sound shallow and empty to you But these are the types of things that narcissists value That's what's important to the narcissist They respect money and power They respect expensive things They respect powerful and attractive people And you can defeat the narcissist With the very things they value and respect So much By achieving those things And then preventing them from gaining access to them Because when it all comes down to it That's really one of the narcissist's greatest fears After everything they've done to you They fear that one day you might achieve everything you've always wanted And everything they've always wanted But after everything they've done to you You're not going to want to share it with them You're not going to want to cut them a piece of the pie Because deep down they know they're not deserving They know they don't deserve to be a part of your life That's why they had to keep you down That'd make you feel like they were better than you Because they already knew That you had the qualities and abilities to achieve great things And that was the last thing they wanted to see One of the narcissist's greatest fears is your potential Your capacity to develop something in the future Because your development equates to the narcissist's relevance Once you become successful And you achieve great things They're no longer relevant Because they were never there for you They didn't support you They didn't invest anything into you So why should they deserve to partake in the fruits of your labour And they know this Which is why the moment they see you progressing in life They know it's all over for them They know they can't come back At that point You have defeated the narcissist Not only because they value superficial things But because of the emotional effects it has on you Success has an emotional effect on us It makes us feel more confident It makes us believe in ourselves It boosts our self-worth and self-esteem And that is the ultimate threat to a narcissist That is what defeats them Your self-love is like kryptonite to a narcissist Which is why the entire time you were with them They tried to keep you down They tried to make you feel like you weren't worthy They tried to put out your light Because they knew that might would eventually reflect on them It would reveal who they are But when you choose to move on with your life And you become stronger and more confident in yourself They become irrelevant They're no longer connected to you As long as you have doubts It gives them an opening to come back Because then they can still have some level of control Over your emotions That's what forms that attachment Because at that point You're in agreement with them that you're not enough But when you're optimistic and self-assured They can't do that They lose They're forced to accept defeat Thank you for watching I hope this video resonate with you Please like, comment, share and subscribe If you would like to donate My PayPal link is in the video description Couching inquiries You can email me and coach an arch-survivor at The Colour UK Thank you for watching And I'll talk to you soon