K-Relevance : A Spectrum Of Relevance For Data Sources Impacting: Fill & Download for Free

NOTE: Keep in mind this a spectrum, not a check list. Somebody whose primarily role is application development with scalability in mind might fit on one end of this spectrum, a distributed systems engineer will fit on the other. If one is passionate about scalable systems, they should have something to show for it: they may not have solved any scalability challenges in their current or previous job, but no one stops them from contributing to open source projects and studying the relevant literature.First, look for general programming skills (algorithms, data structures, excellence in their chosen programming language; CLRS and K&R should be hot in their "page cache"), strong knowledge of systems (concurrency, operating systems internals) and an interest in and excitement for building systems: i.e., building reusable components for other programmers should excite at least as much as (if not more) than building products that end-users interact with (much like you'd want to look for the opposite quality in an application developer).See Kartik Ayyar 's answer in the What are the best interview questions to evaluate a systems programmer? Key thing to look for are: ability to build and reason about complex systems in the face of concurrency challenges and hardware/network limitations, excellent debugging skills. They don't have to be a kernel hacker: having written code that runs in the kernel is neither necessary nor sufficient. Nonetheless, they shouldn't have an irrational fear of systems software: to them, the kernel (or a B+Tree implementation, etc...) should be just another piece of code that they're ready to jump in and debug.A weak programmer can wax eloquently about architectures and high scalability and repeat other companies' war stories, but there are two types of architects: those who code and those who should find another job. Make sure you aren't promoting somebody to their level of incompetence because they happened to memorize a bunch of buzzwords.Second, look for strong knowledge of distributed systems. This post by Werner Vogels is a good example: http://www.allthingsdistributed.com/historical/archives/000538.htmlYou know your distributed systems theory: You know about logical time, snapshots, stability, message ordering, but also acid and multi-level transactions. You have heard about the FLP impossibility argument. You know why failure detectors can solve it (but you do not have to remember which one diamond-w was). You have at least once tried to understand Paxos by reading the original paper.You have a good sense for distributed systems practice: You can reason about churn and locality in DHTs. You intuitively know when to apply ordered communication and when to use transactions. You can reason about data consistency in a system where hundreds of nodes are geographically distributed. You know why for example autonomy and symmetry are important properties for distributed systems design. You like the elegance of systems based on epidemic techniques.You have good common sense about scale and availability: You frown when someone mentions two-phase commit in the same sentence as high-availability. You also realize that protocols that require a system "to be stable for a sufficiently long period of time" are not a good basis for building real systems. You understand the elegance of of state-machine replication, but understand why it is hard to apply at large scale. You have a solid intuition about the impact of design decisions on the ability to achieve data consistency, and you are not scared by the idea of building systems based on 'eventually consistent' data.Some of your heroes have actually built real systems: Worshipping Dijkstra and Lamport is OK as long you also know why Jim Gray and Bruce Lindsay deserve a red carpet. You dream about how much smarter you would become if only Pat Helland would go back to writing on his weblog.You have actually built some real systems yourself. At work or at school, you must have faced some real hard distributed problems and solved them. You are involved in an open-source project that has solid distributed systems components.Keep in mind that distributed systems and systems programming are two different subjects, with entirely different career options (e.g., Java middleware vs. embedded systems) but Internet-scale applications (where costs and latency matter, as do throughput, reliability, scalability and availability) require good understanding of both. An honest engineer should know when it makes sense to scale out and when it makes sense scale up, despite a personal preference for one over the other (e.g., resisting the temptation to do a clever low-level hack when the task is trivially distributable or resist the temptation to build a custom distributed system to processes data that easily fits into a single machine's main memory).Lastly, ask questions that deal with real world scalability problems that they faced ("what was the toughest scalability problem you've solved?") and ask design questions dealing with scaling out systems that aren't key-value stores (design decisions involved in building a key-value store are quickly becoming general knowledge): how would they build a scalable distributed { online [board or card] game, file system } are just some examples. There is a set of questions I like to ask candidates for distributed infrastructure positions, but I won't divulge them here :-)

Yes, T cells mature/develop in the thymus and yes, the thymus shrinks with age through a process called Involution. Occurring in many vertebrates, thymic involution is an ancient and evolutionarily conserved process (1). Let's examine the thymus in step-wise fashion. How does it shrink? Why is it important? Could mouse models be inconsequential for understanding human thymus function? Finally, why does it shrink with age?Before proceeding, let's define a few immunological terms pertinent for this discussion.Peripheral: Immunologists define the thymus as the site of T cell development/maturation. Everywhere else we find T cells, we call the periphery, and naturally, such T cells we call peripheral, as opposed to thymic, T cells.Germline: The key identifier of T cells is their T cell receptor (TCR). Immature T cells start out with a TCR we call germline TCR. During T cell development/maturation, this TCR undergoes re-arrangement through genetic recombination to become entirely different from the one the immature T cell started out with.Senescence: Permanent cell cycle arrest. Hayflick originally identified it in human fibroblasts (2). Senescent cells either no longer divide/can divide. Same concept applied to immune cells is called Immunosenescence (3).Repertoire: Typically refers to the spectrum of unique TCRs (and BCRs; B cell receptor) in an individual. Naive repertoire refers to the spectrum of new (naive) T and B cells and their receptors.How does the thymus shrink with age?Current consensus says thymus shrinks in an age-dependent program. Though the process starts during puberty or even earlier, in middle age adipocytes (fat cells) infiltrate and take over. In short, with age, the thymus changes from a primary lymphoid organ into a fatty tissue (4).C, cortex; M, medullaFrom 5 (figure is based on original data from 6)Why is the thymus important?As the thymus shrinks with age, fewer naive (new) T cells come out of it. The unique feature of T and B cells that renders them responsive to billions of antigens is key for understanding the ramifications of this decline. Somatic, i.e. non-germ (eggs and sperm) cells, usually do not undergo genetic recombination. Uniquely among somatic cells, T and B cells undergo genetic recombination during their development. This happens in the thymus for T cells and in the bone marrow for B cells. As a result of this recombination, mature T cells coming out of the thymus bear re-arranged TCRs, each specific for one antigen (peptide)* out of a vast universe of antigens. A picture is worth a thousand words? With T cells, numbers reveal their awe-inspiring scope. We humans have approximately 3X1011 T cells in circulation, capable of recognizing approximately a billion unique antigens, and our thymus needs to generate approximately 3X109 T cells daily to replenish this circulating pool (7).Coming out of the thymus, T cells circulate in our body, those that get activated by their specific antigen (peptide) expand and become memory T cells while those that don't, die. Let's remember there's a universe of antigens out there, and we don't know ahead of time which ones our T cells would need to respond to. With age, with fewer new T cells coming out of our thymus, the range of antigens recognized by our circulating T cells shrinks and we become less capable of clearing new infections. When thymus is removed (thymectomy) within a few weeks of birth, circulating T cells of even 22 year olds resembled those of 75 year olds (8, 9), suggesting early-life thymus is key for long-term healthy T cell function.The human is not just an overlarge mouse.Mouse models suggest thymus involution weakens T cell function. Does the same hold for humans? Recent data suggests not. Phew! Rather, this mouse-human difference is a difference in kind, not degree.Human naive T cells self-renew from the existing peripheral T cell pool (10).A mathematical (in silico) model (11) also suggests our peripheral T cells self-renew.Our thymus starts to shrink, and reduces T cell output already in our 20s, yet our circulating naive CD4 T cell repertoire stays more or less steady for decades, abruptly collapsing only in our 80s (12, 13). Reasons for this late-age abrupt collapse are still unknown.An important caveat about human studies on T cell function? Most of our data is from circulating blood cells. Problem? Yes, for two reasons.T cells circulating in our blood account for only about 2% of our total T cell pool (14)As Jurgen Westermann, a German immunologist, has argued for years, immune cells don't leave tissues such as bone marrow, spleen, lymph nodes at random to circulate in our blood. They do so in response to specific cues and to perform specific functions.Yet, we freely, egregiously and foolishly extrapolate from circulating T cell function to entire body T cell function.When it comes to aging and immune function, we are left with the inherent contradiction of the less active (immunosenescence) co-existing with the overactive (autoimmunity) (15). How so?With age, our immune function becomes senescent (immunosenescence) and less effective (15). Old age is associated with poor response to vaccinations (16, 17) and to chronic viral infections (18), and much lower acute transplant rejections (19, 20).At the same time, the older we are, more we are prone to autoimmune diseases such as rheumatoid arthritis (21). Autoimmune diseases represent overactive, not less active, immune function.How to deal with this contradiction? Let's examine possible reasons.Maybe elderly with autoimmunity have dysfunctional physiology, and T cells specific for the autoimmune protein targets expand at the expense of vaccine-specific T cells? For e.g., elderly autoimmune T cells have signaling pathway changes that render them more, not less, responsive (15).Maybe elderly do have similar numbers of vaccine-specific T cells, only they are dysfunctional or non-responsive, having undergone specific biochemical changes. Thus, even though immune senescence and autoimmunity appear contradictory on the surface, they have key similarities in specific processes such as chronic DNA damage like telomere erosion (15), though we don't yet have definitive data for this being responsible for T cell aging effects (22).Elderly with poor response to vaccines could have persistent viral infections (23) such as Varicella-zoster, measles, HIV-1, CMV (cytomegalovirus), viruses that, for some reason, are not cleared but persist/reside inside cells such as epithelium, neurons, immune cells, sitting there quietly (latent), popping out every now and then to re-activate virus-specific T cells. Over time, such virus-specific T cells would expand at the expense of other, particularly naive T cells. After all, our body offers a finite space. T cells that get stimulated stick around, those that don't, die.In some elderly, the gut becomes leaky, letting in more microbes and microbial products, which chronically stimulate their T cells, a process evocatively called Inflammaging (24, 25).We finally come to the most important question.Why does the thymus shrink with age?Our thymic T cell output is highest immediately post-birth, and then steadily declines, with little output after 20 years of age. 20! That's not old or elderly by any stretch of the imagination. While an intriguing 1999 study showed adult human thymus had similar thymopoiesis (T cell development) compared to those in fetuses (26), it had two main problems. One, few donors (looks like no more than 4 adult donors). Two, age not specified except to say above 23 years of age. Thus, puberty triggers thymic involution and a study showed it starts even earlier (27). What's the link with puberty? Do sex steroid hormones initiate thymic involution? That's debatable (28). Nevertheless they kill thymocytes (29). Thus, with puberty, there's a sharp decline in thymus tissue. After this sudden sharp reduction, involution continues at a steady rate with about 3% loss per year until middle age, and about 1% loss per year thereafter (30, 31).With age, why does the thymus change from lymphoid tissue into fat? To avoid the danger of mistaking effect for cause, let's recognize that the thymus starts to shrink (involute) long before it gets fat deposits (32). However, aged thymi do indeed have fat deposits, and these adipocytes may secrete cytokines that alter/impair thymic function. Thus, while fat deposition may not start thymic involution, it may help set it in stone, or rather fat.Fat deposition aside, two types of age-associated changes may trigger and/or maintain thymic involution.Bone marrow output decreases. It's the source of hematopoietic stem cells (HSC). This includes T cell progenitor cells which, in response to as yet unknown cues, enter the blood circulation and from there the thymus, and interact with thymic epithelial cells to mature in a strictly defined developmental program. With age, bone marrow output of HSCs including T cell progenitor cells declines (33).The thymus tissue (stroma) becomes fibrotic. Specialized thymic epithelial cells provide signals necessary for thymopoiesis (cell maturation process) and with age, are replaced by fibroblasts (fibrosis; 34). Increasing fibrosis in many organs such as heart, kidney and liver is indeed associated with aging, and may be a common aging signature.Donald B. Palmer and colleagues from the Royal Veterinary College at the University of London in the UK (35, 36) propose an intriguing idea about thymic involution, separating it into a two-stage process. The first one, in puberty, they call “growth dependent thymic involution”, occurring as it does during a period of physiological growth and development. The second one, they call “age-dependent thymic involution”, which occurs in tandem with other age-related changes in the body.Thus, during puberty, we undergo “growth dependent thymic involution”, while the rate and degree of “age-dependent thymic involution” is likely influenced by our genetics and lifestyle choices. For example, many studies suggest moderate physical activity supports and maintains immune function in the elderly (37, 38, 39). How could exercise do this? After all, it doesn't reverse thymic involution per se so it wouldn't increase new T cell output. Maybe exercise correctly balances the milieu in which T cells operate, maybe it leads to healthier lymphatics which help T cells circulate properly and efficiently, maybe it better balances the neuro-endocrine system, helping allay or delay thymic involuting factors such as adipocyte infiltration? Open questions yet.Regardless thymus involution and attendant reduction in new T cell output, we have among us the successfully aged, namely centenarians. What's different about their thymus and their T cells? Data is limited, not extensive.Long-term Swedish studies (40, 41) found centenarians did not have an Immune Risk Profile (IRP). What's the IRP? Inverted circulating CD4 to CD8 T cell ratio. High CD4 to CD8 T cell ratio is considered normal in the young. However, a newer data set from 151 healthy >65 year olds found two other parameters correlated with mortality (42). One was higher levels of a liver-derived protein, C-reactive protein (CRP), indicative of systemic inflammation. The other was lower thymic output, measured using a newer technique called signal-joint T cell receptor (TCR) excision circles (sjTREC). This suggests active thymic output may remain relevant even into late old age.Another centenarian study found genotypic differences in a particular cytokine, IL-10 (43). We immunologists think IL-10 dampens exuberant immunity.Proposed originally in the 1970s by the acclaimed French immunologist, Jean-Francois Bach, the most compelling idea yet about the thymus is a long-forgotten one, that it's an endocrine organ. Unfortunately, we simultaneously discovered that it was also the site of T cell development, and since then its thymopoiesis function became the research focus at the expense of its endocrine function (44). For example, as an endocrine gland, the thymus secretes thymulin. Discovered and characterized by Bach, it's a metallopeptide that, among other things, mediates thymus-pitutary communication (44). Thymus as an endocrine gland throws up many more open questions about its function. Circadian rhythms, seasonal changes, sex differences in autoimmunity. Careful, extensive and imaginative inter-disciplinary study of the centenarians among us will help resolve the mystery of thymus function in healthy aging.BibliographyShanley, Daryl P., et al. "An evolutionary perspective on the mechanisms of immunosenescence." Trends in immunology 30.7 (2009): 374-381.Page on google.com=Page on nih.govPage on nih.govPage on nih.govLeukemia Inhibitory Factor, Oncostatin M, IL-6, and Stem Cell Factor mRNA Expression in Human Thymus Increases with Age and Is Associated with Thymic AtrophyGoronzy, Jörg J., and Cornelia M. Weyand. "T cell development and receptor diversity during aging." Current opinion in immunology 17.5 (2005): 468-475.Page on nih.govPage on nih.govPage on sciencedirect.com)Johnson, P.L.,Yates, A.J.,Goronzy, J.J., and Antia, R.(2012). Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age. Proc.Natl.Acad. Sci.U.S.A. 109, 21432–21437. doi:10.1073/pnas.1209283110.Page on jimmunol.orgCzesnikiewicz-Guzik, M.,Lee, W.W., Cui, D.,Hiruma, Y.,Lamar, D. L., Yang, Z.Z.,etal.(2008).T cell subset-specific susceptibility to aging. Clin. Immunol. 127, 107–118. doi:10.1016/j.clim.2007.12.002Di Rosa, Francesca, and Reinhard Pabst. "The bone marrow: a nest for migratory memory T cells." Trends in immunology 26.7 (2005): 360-366.The Janus Head of T Cell Aging - Autoimmunity and ImmunodeficiencyPage on jimmunol.orgPage on oxfordjournals.orgSevere cytomegalovirus infection in apparently immunocompetent patients: a systematic reviewBradley, Benjamin A. "Rejection and recipient age." Transplant immunology 10.2 (2002): 125-132.Trzonkowski, Piotr, et al. "Immunosenescence increases the rate of acceptance of kidney allotransplants in elderly recipients through exhaustion of CD4< sup>+</sup> T-cells." Mechanisms of ageing and development 131.2 (2010): 96-104.Page on nih.govPage on nih.govHuman T Cell Aging and the Impact of Persistent Viral InfectionsFranceschi, Claudio, et al. "Inflamm‐aging: an evolutionary perspective on immunosenescence." Annals of the New York Academy of Sciences 908.1 (2000): 244-254.Page on www.ideal-ageing.eu)Page on cell.comSteinmann, G. G., B. Klaus, and H‐K. MÜLLER‐HERMELINK. "The involution of the ageing human thymic epithelium is independent of puberty." Scandinavian journal of immunology 22.5 (1985): 563-575.Montecino-Rodriquez, Encarnacion, Hyeyoung Min, and Kenneth Dorshkind. "Reevaluating current models of thymic involution." Seminars in immunology. Vol. 17. No. 5. Academic Press, 2005.The Effect of Age on Thymic FunctionSteinmann, G. G. "Changes in the human thymus during aging." The Human Thymus. Springer Berlin Heidelberg, 1986. 43-88.George, Andrew JT, and Mary A. Ritter. "Thymic involution with ageing: obsolescence or good housekeeping?." Immunology today 17.6 (1996): 267-272.Page on nih.govPage on nih.govBertho, Jean-Marc, et al. "Phenotypic and immunohistological analyses of the human adult thymus: evidence for an active thymus during adult life." Cellular immunology 179.1 (1997): 30-40.Aw, Danielle, and Donald B. Palmer. "It’s not all equal: a multiphasic theory of thymic involution." Biogerontology 13.1 (2012): 77-81.The Effect of Age on Thymic FunctionPhysical Activity and Hemostatic and Inflammatory Variables in Elderly Men; Page on google.com=The influence of exercise on brain aging and dementiaPage on dcconferences.com.auOlsson, Jadwiga, et al. "Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study." Mechanisms of ageing and development 121.1 (2001): 187-201.Page on tara.tcd.iePage on nih.govPage on nih.govPage on nih.gov* The antigens T (and B) cells respond to (their specificity) is a much more complicated story, and incomplete without considering cross-reactivity, another topic altogether.

This answer is a collaboration between Athena Walker and Dr. Natalie Engelbrecht, BA MSc ND RP. As such it is divided between two posts. The first half is presented in Athena Walker’s post with a link to Natalie Engelbrecht and the second half is presented in Natalie Engelbrecht’s post with a link to Athena Walker’s. Please start with Athena Walker’s post. Both posts were a collaboration, with neither being written solely by either individual.Part 1 of 2: Athena Walker's answer to What is the latest research on brain structure, chemistry, physiology and genetics as well as emerging theories regarding psychopathy?What is the latest research on brain structure, chemistry, physiology and genetics as well as emerging theories regarding psychopathy? Part 2 of 2Changes to Specific Areas of the Brain that Relate to PsychopathyAmygdalaLocation: Studies have revealed that the amygdala is not a homogeneous structure and can be differentiated into approximately 13 nuclei. Although the functional specificity of the nuclei in the human amygdala remains unclear, considerable evidence from animal studies suggests that several nuclei of the amygdala are involved in the processing of emotion. For example seminal research demonstrated that monkeys with damaged amygdalas have been shown to lack fear cue processing, and attempt to pick up live cobras.Function: Significant correlations were found between reduced amygdala volumes and increased total and facet psychopathy scores, with correlations strongest for the affective and interpersonal facets of psychopathy.Psychopath Phenology: Individuals with psychopathy showed significant bilateral volume reductions in the amygdala compared with controls (left, 17.1%; right, 18.9%). Surface deformations were localized in regions in the approximate vicinity of the basolateral, lateral, cortical, and central nuclei of the amygdala.This article introduces a novel hypothesis regarding amygdala function in psychopathy. The first part of this article introduces the concept of psychopathy and describes the main cognitive and affective impairments demonstrated by this population; that is, a deficit in fear-recognition, lower conditioned fear responses and poor performance in passive avoidance, and response-reversal learning tasks. Evidence for amygdala dysfunction in psychopathy is considered with regard to these deficits; however, the idea of unified amygdala function is untenable. A model of differential amygdala activation in which the basolateral amygdala (BLA) is underactive while the activity of the central amygdala (CeA) is of average to above average levels is proposed to provide a more accurate and up-to-date account for the specific cognitive and emotional deficits found in psychopathy. In addition, the model provides a mechanism by which attentional-based models and emotion-based models of psychopathy can coexist. Data to support the differential amygdala activation model are provided from studies from both human and animal research. Supporting evidence concerning some of the neurochemicals implicated in psychopathy is then reviewed. Implications of the model and areas of future research are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).A model of differential amygdala activation in psychopathy.InsulaLocation: Located deep in the cerebral cortex.Function: Processing of disgust cues is not believed to rely upon amygdala; rather the relevant circuitry is thought to be the anterior insular cortex. The insula exhibits higher activity when neurotypicals make decisions and difficult personal moral dilemmas that they consider as repugnant acts.Psychopath Phenology: Hypofunctioning in psychopathy.Nucleus AccumbensLocation: In the basal forebrain rostral to the preoptic area of the hypothalamus.Function: Plays a central role in the reward circuit. Its operation is based chiefly on two essential neurotransmitters: dopamine (promotes desire), and serotonin (satiety and inhibition).Psychopath Phenology: The volume of the nucleus accumbens was 13% smaller in psychopathy. The atypical morphology consisted of predominant anterior hypotrophy bilaterally.Orbitofrontal CortexLocation: The part of the prefrontal cortex that is positioned directly over the orbits or eye sockets. It is located at the base of the frontal lobe.Function: Social interactions, inhibition of impulsive behavior, ethics, morality, reward and punishment, regret, and projection of future outcomes based on implied expectations of planned near term actions. Involved in the regulation of many social functions, which include ethics and morality.Psychopath Phenology: Lower activity in psychopathy.Note: The terms Orbitofrontal Cortex and Prefrontal Cortex in research are sometimes used interchangeably, and at other times, ‘ventromedial prefrontal cortex’ is used to describe a broad area in the lower (ventral) central (medial) region of the prefrontal cortex, of which the medial orbitofrontal cortex constitutes the lowermost part.Ventromedial Prefrontal Cortex (Lower)Location: The frontal lobe, located at the front of the brain, is one of the four major lobes of the cerebral cortex.Function: The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex. The dopamine system is associated with reward, short term memory, planning and motivation. The function of the frontal lobe involves the ability to project future consequences resulting from current actions, the choice between good and bad actions (or better and best) (also known as conscience), the override and suppression of socially unacceptable responses, and the determination of similarities and differences between things or events. The vmPFC is critical in regulating emotion, threats, decision-making and social behavior. Furthermore, the vmPFC also plays an important part in integrating longer non-task-based memories stored across the brain. These are often memories associated with emotions derived from input from the brain’s limbic system. The frontal lobe modifies those emotions to generally fit socially acceptable norms. It is known as the ethics and morality section of the brain.Psychopath Phenology: Notice that the normal scan shows much more activity (yellow and red) in the lower frontal lobe than Fallon’s (mostly blue).ConclusionBrain structural and functional changes in psychopathy suggest that psychopathic individuals have a different way of seeing the world. Further research suggests they may use alternative strategies—such as cognitive empathy and rationality—more than neurotypicals use to make moral judgments. Much of the current research presents psychopathy brain alterations as pathological. Words like “healthy people” (meaning neurotypicals), “brain damage” and “brain dysfunction” serve to bias readers and researchers to view psychopathy as a dysfunction. As psychopathy is inherited and not caused by environmental triggers such as abuse, the word variant may be a better alternative, and lead to less bias.Brain Chemistry Difference of Psychopathy.High resolution PET and fMRI scans suggest that alterations in the function of the brain’s reward system may contribute to psychopathy.Research indicates that dopamine genes leading to alterations in an increased amount of dopamine released in comparison with neurotypicals brains is associated with psychopathy. In fact research indicated that psychopaths release four times more dopamine in the nucleus accumbens than neurotypicals.Dopamine plays important roles in executive functions, motor control, motivation, arousal, reinforcement, and reward. Studies found that increases in dopamine resulted in a trait aggression and impulsive-antisocial psychopathic traits. Further, an increase in dopamine reduces a hyper-altruistic tendency, altering it to prefer harming others over harming oneself.Research of the gene 5-HIAA also indicates lower levels of serotonin occur in psychopathy. Studies demonstrated that a decrease in serotonin resulted in a decrease in harm aversion for both self and others.Psychopathy also demonstrates higher methylation of oxytocin resulting in lower oxytocin levels. Lower circulating oxytocin results in decreased in interpersonal empathy. Although known for increasing bonding and trust, recent studies found that people who were given oxytocin had more envy and gloating during a game of chance. It appears that oxytocin increases both negative and positive emotions. Thus researchers are unclear as of yet whether the effect on increasing oxytocin will be to make a psychopath more social, as well as enhancing anger and aggression.Genes:IntroductionFourteen years ago (2003) the human genome was fully sequenced (in the year 2000 a rough draft was first identified). With this momentous discovery, the genetic basis of some of the most common disorders have begun to be revealed. One area of such research has been the genetics associated with psychopathy. Twin studies do support that psychopathy is strongly heritable. However no single SNP has shown a large or even moderate effect size for psychopathy. The idea of nature/ nurture is outdated. Instead it seems the effect of genes for psychopathy appears to be both polymorphic (tendencies are conferred by multiple genes of small effect size that probabilistically increase the risk for poor behavioural outcome), as well as epistatic (where one gene interacts with another gene at a different location) and epigenetic (environmental buffers that can be used to moderate the effects of risk genes).There are no good genes or bad genes, but there are alleles that are associated with violence and also a lack of empathy. For example antisocial behaviour (AB) is strongly heritable for callous-unemotional traits in children. AB+/ CU+ children show low emotional reactivity to punishment and distress, as well as poor ability to empathize with others. On the other hand non-callous AB (AB+/CU–) children show mainly environmental influences for their antisocial behaviour. They are emotionally reactive to threat, and are created via environmental risk influences (such as harsh parenting) epigenetically driving the expression of antisocial behaviour for this group. However, certain genes create a significant risk for violence when activated via appropriate epigenetic factors. Studies demonstrate that it is unlikely that genes directly code for violence; rather, allelic variations are responsible for individual differences in neurocognitive functioning that, in turn, may determine differential predisposition to violent behavior. Of the genes associated with psychopathy, MAOA-L is the most well-known and was among the first evidence that the variant MAOA-L interacts with childhood maltreatment to modulate antisocial tendencies (Caspi et al, 2002). “Specifically, severely maltreated participants carrying the low-activity allele of the MAOA gene displayed the highest scores in disposition toward violence and antisocial personality disorder scores, and demonstrated the greatest proportions of adolescent conduct disorder and convictions due to violent behavior.” (Buades-Rotger & Gallardo-Pujol, 2014). Recent research suggests that genetic vulnerability to violence conferred by the low-activity allele of MAOA-L variant may only become evident in the presence of environmental triggers of maltreatment. In favorable conditions, genetic predisposition alone may be of little consequence for behavior.Gene & Their Associated SNPs (alphabetical order)5-HTTLPR (serotonin transporter gene)SNP: rs25531 (G;G) The long allele of the serotonin transporter gene is a potential risk factor for psychopathy. It is associated with less pain sensitivity.ARL6IP6 (ADP-ribosylation-like factor 6 interacting protein 6 )Associated with autistic psychopathy (form of autism spectrum disorder that is less severe than other forms, characterized by difficulty with social interaction and communication and by repetitive behavior or restricted interests) in childhood.SNP rs11682518DRD2 and DRD4Positively correlated with a continuously coded psychopathic personality traits scale.HTR1B (Serotonin 1B Receptor Gene)Serotonin 1B Receptor Gene (HTR1B)Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys. One neurochemical system that has been implicated both theoretically and empirically in CU traits and psychopathy is the serotonin system. For example, recent research identified an association between SNPs in the genes encoding serotonin receptor 2A (HTR2A) and serotonin receptor 1B (HTR1B) as well as CU traits in children with antisocial behaviour problems.HTR1B is of particular interest because it has been found to be linked with behaviors and characteristics commonly associated with CU traits. Most notable are the animal studies which have demonstrated that mice without the serotonin 1B receptor gene show significantly elevated levels of aggression and lower levels of anxiety; both of which are typically associated with psychopathy. Studies in humans have also found an association between HTR1B and impulsive aggression, suggesting that serotonin 1B receptors may be involved in the control of aggression and impulsivity in humans.SNP rs11568817 (T;T)Associated with traits linked with ‘psychopathy’ including alcohol dependence, self-reported anger and hostility in young men, and autism spectrum disorder which is characterized by deficits in empathy that overlap those found in people with high CU traits. However, as psychopaths have been shown to be immune to dependence on addictive substances, it is unclear whether this gene is present in psychopathy, or if it may be a genetic marker for ASPD, which does have significant issues with substance dependence.HTR2A (serotonin receptor 2A)Provoked aggression associated with primary psychopathy traits. Hostility, Anger and Physical Aggression—but not verbal aggression—were associated with this gene, but only for provoked incidents.SNP rs7322347 (T;T)MAOA-L (Monoamine oxidase A)“MAO-A has been named the ‘warrior gene’, and also more unfavourably the ‘psycho gene’. The gene is a variation of a gene on the X chromosome and therefore inherited from your mother. Females have two X chromosomes and males have an X and a Y chromosome. Mothers always pass an X chromosome on to their children. While if a father passes on his X chromosome (leading to a pair of X chromosomes and a female offspring) or his Y chromosome (leading to one X and one Y chromosomes and a male offspring).This variation occurs in the X chromosome gene that produces monoamine oxidase A (MAOA), an enzyme in the brain that breaks down the neurotransmitters such as noradrenaline, adrenaline, serotonin, and dopamine.People with the low-activity MAO-A gene (2R, 3R) are overall more prone to violence, impulsiveness and aggression. Specifically, when people with the MAOA-L feel very provoked or socially isolated their aggression will come out. Again, from an evolutionary perspective, this makes sense; a warrior needs to respond to threat, rather than act in a chaotic manner. Research demonstrates that low-activity MAO-A people are more likely to take revenge for someone who does something to leave them in a bad situation; however they do not act on small misdeeds.Those with MAOA-L also showed hyperresponsiveness of the amygdala during tasks such as copying facial expressions. This accounts for an increased ability in this group to recognize emotions and also mimic them (the psychopathic mask).”Natalie Engelbrecht's answer to What are the effects of having MAOA?What are the effects of having MAO-A? Scientists believe it leads to impulsive behavior (such as as hypersexuality), sleep disorders, mood swings, and violent tendencies.SNP: rs909525: Warrior; M: C= 3 allele; F: CC= 3 alleleSNP: rs12551906(G;G)SNP: rs10865864 (G;G)SNP: rs151997 (T;T)OXTR (oxytocin receptor gene)Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy. Evidence suggests that epigenetic changes in the OXT receptor gene (OXTR) are associated with lower circulating OXT and social–cognitive difficulties. Oxytocin promotes emotional and cognitive aspects of empathy; however increasing oxytocin can have the effect of increasing aggression.SNP: rs53576 (A;A) Associated with lack of empathy.SNP: rs2254298 (A;A) Smaller amygdala volume, both right and left sides.SNP: rs1042778(T;T) Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy.SNP: rs237887 (A;A) Lower emotional empathy.SNP: rs4686302 (T;T) Lower emotional empathy.Other Top Potential SNPs: rs124111132; rs7531603; rs2514788; rs4383690; rs6846114; rs2376016; rs2311846; rs11088618; rs41516949; rs7640807; rs1490666; rs293844; rs4241597; 6446569; rs1441990; rs1893815; rs11637779; rs10859716; rs1785633; rs4479686; rs10050093; rs12647756; rs1345959; rs13064369; rs8059321; rs6560704In conclusionEmerging research in psychopathy has begun to focus on psychopathy as a normal variant of neurotypical personality and brain function. Genetic brain scans and brain chemistry are all lending to this turn in the tides form psychopathy as a mental illness to psychopathy as a unique personality.SummaryPsychopathy is a distinct personality variation. In psychology, psychopathy is referred to as a personality disorder, often associated with criminal behaviour, however researchers are now arguing that psychopathy is a neurological variation.Researchers in the area of psychopathy have stated that psychopathy does not equal ASPD, but that ASPD is a behavior that may co-occur in some with psychopathy.The preferred method of assessment is no longer the PCL-R, but instead is now the PPI-R. It is intended to measure the psychopathic personality traits on a spectrum, without assuming particular links to antisocial or criminal behaviors. The test has been standardized to a non-prison population.Emerging research in genetics shows that MAOA-L has a significant role in psychopathy, however psychopathy is polygenetic, and it is the interplay of the genes and the effects of the environment that creates the person.Brain scan images demonstrate a smaller amygdala, a lower activity PFC, and a down-regulated pathway between the two in psychopathy, along with other brain changes.Areas such as the insula and nucleus accumbens are also different in psychopathy. An increased amount of dopamine is released in psychopathy in comparison with neurotypicals. Serotonin levels and oxytocin levels are lower in psychopathy.References:Buades-Rotger, M., & Gallardo-Pujol, D. (2014). The role of the monoamine oxidase A gene in moderating the response to adversity and associated antisocial behavior: a review. Psychology research and behavior management, 7, 185.Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., ... & Poulton, R. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297(5582), 851–854Dutton, K., & McNab, A. (2014). The Good Psychopath's Guide to Success. Random House.Viding, E., Hanscombe, K. B., Curtis, C. J., Davis, O. S., Meaburn, E. L., & Plomin, R. (2010). In search of genes associated with risk for psychopathic tendencies in children: a two‐stage genome‐wide association study of pooled DNA. Journal of child psychology and psychiatry, 51(7), 780–788.Sources:http://www.dailymail.co.uk/news/article-3230167/Is-child-psychopath-Traits-lack-emotion-empathy-detected-just-THREE-years-old.htmlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124068/http://www.sciencedirect.com/science/article/pii/S0149763410001181https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933872/https://www.ncbi.nlm.nih.gov/pubmed/23874384?dopt=Abstracthttps://www.ncbi.nlm.nih.gov/pubmed/23874384?dopt=Abstracthttps://www.ncbi.nlm.nih.gov/pubmed/21208749?dopt=Abstracthttps://www.ncbi.nlm.nih.gov/pubmed/22357335?dopt=Abstracthttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065789http://www.independent.co.uk/news/science/ten-years-ago-today-it-was-revealed-that-the-human-genome-had-been-decoded-a-medical-revolution-2011016.htmlhttp://www.bremertonschools.org/cms/lib/WA01001541/Centricity/Domain/222/Psychopaths%20How%20Can%20You%20Spot%20Once%20article%201415.pdfhttp://moritzlaw.osu.edu/osjcl/Articles/Volume3_2/Symposium/Fallon-PDF-03-29-06.pdfhttp://www.businessinsider.com/what-a-psychopath-brain-looks-like-2015-7http://www.sciencedirect.com/science/article/pii/S0960982215005953http://www.sciencedirect.com/science/article/pii/S0047235213000238http://psychnews.psychiatryonline.org/doi/10.1176/pn.45.9.psychnews_45_9_022https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603572/http://www.jneurosci.org/content/31/48/17348http://www.psychologicalscience.org/news/releases/the-dark-side-of-oxytocin.html#.WLQ_qhLyuRshttps://www.researchgate.net/publication/232579271_Psychic_blindness_and_other_symptoms_following_bilateral_temporal_lobectomy_in_Rhesus_monkeyshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458834/Edits:From Q&A in commentsQuestion 2. from: Martin Silvertant“You need both the genes and changes in brain pattern to result in psychopathy. By themselves neither will result in psychopathy.”Could you elaborate on this? What would one without the other do?Martin SilvertantEpigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207041/Answer: Athena Walker & Natalie EngelbrechtEpigenetics is revolutionizing how scientists think about genetics. Epigenetics refers to external changes to DNA that turn genes “on” or “off” without altering the DNA sequence. Gene expression—the manifestation of genetic potential—is modified in epigenetic processes, even though the gene itself stays intact.The research indicates:gene + brain changes =psychopathygene + 0 brain changes = NT who has increased resilience to stress (monoamine oxidase A (MAOA)-COMT interaction that affects endocrine responses to a psychological challenge)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833107/#R580 + brain changes = pseudopsychopathy; brain changes due to early (teen) drug abuse, trauma, etc.Question 4. from: Martin Silvertant“As psychopathy is inherited and not caused by environmental triggers such as abuse, the word variant may be a better alternative, and lead to less bias.”I agree dysfunctional is not a proper term to describe psychopathy, although it seems that should depend on whether the individual is leading a dysfunctional life. Perhaps you would rather assign that term to ASPD than psychopathy in that case. However, in Athena’s answer you spoke of disorder not being a proper term, and I’m not sure I can agree with that. It depends on how you contextualize it. A disorder seems to be defined as a “disruption of the systematic functioning or neat arrangement of” the brain, so when compared to a neurotypical I reckon psychopathy can be defined as a disorder, though that term may not be meaningful to the individual. On the other hand, I wonder if the psychopath’s feelings on this matter are relevant, as by definition they would not experience their pathology as a disorder. For me as an autistic individual it’s different, because I struggle where Athena would not. Not struggle in the same sense, in any case, my autism is likely inherited as well. Should autism then be considered a variant? I don’t quite follow this line of reasoning. I understand you want to prevent bias, but I fail to see how calling it a variant is making a difference, or describing it more accurately. Variant, disorder, dysfunction—it’s a deviation from neurotypical functioning, either way.Martin SilvertantAnswer: Athena Walker & Natalie EngelbrechtThe answer to Q&A #3 (located on Athena’s post, answers this question. It has been copied here for ease).The issue with conflation rests not here in the paper, but in the very dilemma that psychopathy faces currently as to what it is, and how it should be considered. So long as the argument can be made that the majority of the people with this variant should be defined by the minority that have antisocial traits as a core feature of their personality, the conflation cannot and will not disappear.The word at its root, psychopathy is not an informative word for the neurological condition, and yet it is the one that we are constrained by. The word originates from Greek psycho- , meaning and spirit, soul, mind; and -pathy again Greek, where it meant “suffering,” “feeling” ( antipathy; sympathy); in compound words of modern formation, often used with the meaning “morbid affection,” “disease”. So the very word means mind disease. The issue of course other than it’s very definition being related back to a disorder, it that there is no differentiation between those that are identified for their actions that are antisocial, and those that will never see the inside of a courtroom.What’s to be done about this? At the moment there is little that can be done without a consensus that the word is inadequate to describe something that is a neurological formation without the assumed standardized criminal features. I think it is appropriate that the word psychopathy stay along with the notion of the brain formation that includes the antisocial manifestations and another, more accurate term be found to address what is being called pro-social psychopathy presently. It cannot be ignored that the majority of the understanding directed at psychopathy is from the side that views it as a disorder, a malfunction, and something that at it’s core is a toxic entity. The newest voice is the smallest, and easily shouted down currently in terms of it being taken seriously. Anything other than disorder, disruption or variant, it’s a conflation, that at its inception is a beleaguered castle. New terminology stands against the ramparts of the old mentality, while the accepted understandings assault new information. Not for being wrong, but for the crime of disagreement.If we look throughout history, we see many people prosecuted for what the masses disagree with. For example Pope Paul V ordered Galileo,to abandon the opinion that heliocentrism (the planets revolve around the sun) was physically true. Galileo was found "vehemently suspect of heresy", namely of having held the opinions that the Sun lies motionless at the centre of the universe, that the Earth is not at its centre and moves, and sentenced to formal imprisonment at the pleasure of the Inquisition. He remained under house arrest for the rest of his life.Helicobacter pylori, or H. Pylori is the cause of ulcers. This is known medical science that seems to go without question. This was not always the case. Back in the late seventies when this was a thought in two doctors’ minds, and they pressed forward to have it be accepted into general medical understanding when they hit an absolute stone wall. Their theory called preposterous and the paper that they wrote with their findings was rejected. It took many years, and one of the two doctors to do the unthinkable, make himself the human guinea pig ingesting a drink infested with the bacteria, and having an ulcer as the result. In time with dogged determination their theory was proven to the rest of the world. In 2005 Barry Marshall and Robin Warren won the Nobel Prize in physiology or medicine delivering a permanent blow to the established assumptions regarding the human body.Operations without anesthetic:, Letter by an Dr. George Wilson , Edinburgh doctor in the 1850’s to the prominent advocate of anaesthesia, the famous obstetrician, Dr Simpson.Pain was not just an unavoidable side effect of surgery. Most surgeons operating in a pre-anaesthetic era believed it was a vital stimulant necessary for keeping the patient alive. This is why opiates and alcohol were used sparingly, and typically administered shortly before (not during) a procedure, as the loss of consciousness was considered to be extremely dangerous.George Wilson—a Professor of Chemistry at Edinburgh University—underwent a foot amputation in 1842. He remembered ‘the fingering of the sawed bone; the sponge pressed on the flap; the tying of the blood-vessels; the stitching of the skin; and the bloody dismembered limb lying on the floor’.“I have recently read, with mingled sadness and surprise, the declarations of some surgeons that anesthetics are needless luxuries, and that unendurable agony is the best of tonics. Those surgeons I think can scarcely have been patients of Those surgeons, I think, can scarcely have been patients of their brother surgeons, and jest at scars only because they have never felt a wound; but if they remain enemies of anesthetics after what you have written, I despair of convincing them of their utility.” (p 210)“Of the agony it occasioned, I will say nothing. Suffering so great as I underwent cannot be expressed in words, and thus fortunately cannot be recalled. The particular pangs are now forgotten; but the black whirlwind of emotion the horror of the black whirlwind of emotion, the horror of great darkness, and the sense of desertion by God and man, bordering close upon despair, which swept through my mind and overwhelmed my heart, I can never forget, however gladly I would do so I would do so.” (p 211)“For a long time they haunted me, and even now For a long time they haunted me, and even now they are easily resuscitated they are easily resuscitated; and though they ; and though they cannot bring back the suffering attending the cannot bring back the suffering attending the events which gave them a place in my memory, they can occasion a suffering of their own, and be the cause of a disquiet which favours neither the cause of a disquiet which favours neither mental or bodily health mental or bodily health... (p 214) ... (p 214)The static mindset of many in the medical and psychological communities can be the largest barrier in the advancement of knowledge. How this status quo is allowed to go on is something difficult to grasp. Like a great Orobus consuming itself, it is a chain that needs breaking so new ground can be broken. For the moment however we have a stalemate that has been reached.Standing in their concrete shoes, many on the psychological side refuse to give an inch. Redefining, reeducating, and rebranding the brain formation as a variant, instead of either a disorder or a disruption would make a good deal of headway in the more moderate community that is unaware that there is even a war happening. Those that are steadfast and stubborn will be cleared away in time, and hopefully more level headed and logical replacements, with cross field interests take their place to provide a clearer ground for understanding. First however, the bloated corpse of ASPD needs to be cleared off the battlefield before a step towards a truce can be made.Athena Walker & Natalie EngelbrechtQuestion 6. from: Martin Silvertant“Associated with autistic psychopathy”My goodness. Why would you use such a long-depreciated term that risks being conflated with psychopathy? Is there a reason why you’re not calling it Asperger’s syndrome or high-functioning autism?Martin SilvertantAnswer: Athena Walker & Natalie EngelbrechtThe term autistic psychopathy was formerly used to mean Asperger’s, however in the literature it now literally means ASPD + Autism. We will likely remove that gene from the final paper as it is referring to ASPD, not psychopathy.Question 8. from: Martin Silvertant“Even Kevin Dutton who dared to find positive aspects of psychopathy and lectures on it is called a maverick. He is a tenured psychology research professor at Oxford University, one of the most prestigious universities in the world. Despite this he is not only ignored, but often attempts to dismiss his work over understanding is the norm.”So when you say “the preferred method of assessment is no longer the PCL-R”, you mean according to Dutton and Blair, right? If so, I would say you are probably mischaracterizing the field. I understand this is where the assessment criteria should be headed, but to my knowledge it’s not (yet) the preferred method of assessment.Martin SilvertantAnswer: Athena Walker & Natalie EngelbrechtThe preferred method for diagnosing what is known as Psychopathy. The PCL-R works well for Psychopathy with ASPD. The PCL-R is never used outside prison walls. It is an assessment meant for use only on the criminal population and is far-leaning to antisocial traits over psychopathic traits. It has garnered a great deal of criticism for this, and its sister test, the PCL-SV is not honed much better for a non-criminal population.