Neuroscience

Important Factors for Regulating the Body’s Immune Response – Neuroscience News

Summary: Researchers identified differences in isoforms that control Treg cells and how that affects the bodys immune system response.

Source: Indiana University

Researchers atIndiana University School of Medicineare learning more about how special regulatory T cells can impact the immune systems response and how those cells could be manipulated for potential treatments for food allergies and autoimmune diseases.

Ina study recently published inScience Immunology,researchers focused on regulatory T cells, or Treg cells, that regulate immune responses in the body and keep the immune system in order while fighting pathogens.

In some cases, the immune system becomes overly responsive, leading to autoimmune diseases, such as Type 1 diabetes or lupus, food allergies or other issues. Researchers were able to identify the differences in isoforms that control Treg cells and how that affects the bodys immune function.

There is a particular gene that controls this regulatory group of T cells, which controls immune response, saidBaohua Zhou, PhD, lead author of the study and associate professor of pediatrics forIU School of Medicine Department of Pediatrics.

Treg cells can help maintain the right balance to help the immune system not respond too strongly or too weakly.

The human gene FOXP3 produces two major isoforms through alternative splicinga longer isoform and a shorter isoform.

The two isoforms are naturally expressed in humans, but their differences in controlling regulatory T cell phenotype and functionality has been unclear. In this study, researchers showed patients expressing only the shorter isoform fail to maintain self-tolerance and develop issues like immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome.

They uncovered different functions of the FOXP3 isoforms to regulate Treg cells and immune homeostasis.

Now that we know the different functions of the isoforms, we hope to study how to change them, which could lead to new treatments for autoimmune diseases and allergies, Zhou said.

We could also potentially manipulate them to keep the body from responding improperly to diseases like cancer. If T reg cells are suppressing the antitumor response, can we change that?

Author: Christina GriffithsSource: Indiana UniversityContact: Christina Griffiths Indiana UniversityImage: The image is in the public domain

Original Research: Closed access.FOXP3 exon 2 controls Treg stability and autoimmunity by Baohua Zhou et al. Science Immunology

Abstract

FOXP3 exon 2 controls Treg stability and autoimmunity

Differing from the mouseFoxp3gene that encodes only one protein product, humanFOXP3encodes two major isoforms through alternative splicinga longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 E2).

The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear.

In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.

Mice withFoxp3exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 E2 are unstable and sufficient to induce autoimmunity when transferred intoTcrb-deficient mice.

Mechanistically, the FOXP3 E2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators ofFoxp3without altered binding to these gene loci.

These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Tregstability and immune homeostasis.

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Important Factors for Regulating the Body's Immune Response - Neuroscience News

Neuroscience

Gekko partners with CloudArmy on neuroscience – Research Live

UK Customer experience marketing agency Gekko has partnered with behavioural insight firm CloudArmy on a neuroscience research service for brands.

The partnership will see both companies work on a number of neuroscience techniques to help examine unconscious and conscious reactions to test a range of attributes, including brand recognition, responses to brand assets and brand perception.

CloudArmy runs a global online methodology that tests measure responses using smartphones to test stimuli and rapid responses and lexical decision making.

A trial of the partnership with 200 respondents will be used to help Gekko advise brands on in-store displays and messaging.

Daniel Todaro (pictured), managing director at Gekko, said: We are delighted to announce this pioneering service, combining our expertise in retail customer journeys and experiences with CloudArmys neuroscience insights.

Neuroscience is the new frontier of understanding human behaviour and this technology truly enables brands to uncover the truth about what customers really think about your brand, as opposed to what they might say.

Thom Noble, president at CloudArmy, said: We are thrilled to be partnering with Dan and his talented team to collaborate on deeper-level evaluation and optimisation of strategy and design.

We believe the blending of science-based approaches helps augment the creativity of interventions to deliver more compelling and powerful experiences and behavioural nudges.

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Gekko partners with CloudArmy on neuroscience - Research Live

Neuroscience

Researchers Uncover New Pathway for Accumulation of Age-Promoting ‘Zombie Cells’ – Neuroscience News

Summary: Oxidative damage to telomeres can trigger cellular senescence. The findings could lead to the development of new therapeutics for healthy aging and to combat cancers.

Source: University of Pittsburgh

Senescent cells those that have lost the ability to divide accumulate with age and are key drivers of age-related diseases, such as cancer, dementia and cardiovascular disease.

In a new study, a team led byUniversity of PittsburghandUPMC Hillman Cancer Centerresearchers has uncovered a mechanism by which senescent, or zombie, cells develop.

Published today inNature Structural & Molecular Biology, the study shows for the first time that oxidative damage to telomeres the protective tips of chromosomes that act like plastic caps at the end of a shoelace can trigger cellular senescence. These findings could eventually point to new therapeutics that promote healthy aging or combat cancer.

Zombie cells are still alive, but they cant divide, so they dont help replenish tissues, said senior authorPatricia Opresko, Ph.D., professor of environmental and occupational health and of pharmacology and chemical biology at Pitt.

Although zombie cells dont function properly, theyre not couch potatoes they actively secrete chemicals that promote inflammation and damage neighboring cells. Our study helps answer two big questions: How do senescent cells accumulate with age, and how do telomeres contribute to that?

When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosomes tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a persons lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a zombie-like state.

Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could turn cells into zombies.

Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome.

Our new tool is like a molecular sniper, explained first author Ryan Barnes, Ph.D., a postdoctoral fellow inOpreskos lab. It creates oxidative damage exclusively at the telomeres.

To develop such marksman-like precision, the team used a special protein that binds exclusively to telomeres. This protein acts like a catchers mitt, grabbing hold of light-sensitive dye baseballs that the researchers tossed into the cell.

When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.

Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a zombie state after just four days much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab.

We found a new mechanism for inducing senescent cells that is completely dependent on telomeres, explained Opresko, who also co-leads the Genome Stability Program at UPMC Hillman. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones.

Sunlight, alcohol, smoking, poor diet and other factors generate reactive oxygen molecules that damage DNA. Cells have repair pathways to patch up DNA lesions, but, according to Opresko, telomeres are exquisitely sensitive to oxidative damage. The researchers found that damage at telomeres disrupted DNA replication and induced stress signaling pathways that led to senescence.

Now that we understand this mechanism, we can start to test interventions to prevent senescence, said Barnes. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.

The findings could also inform the development of new drugs called senolytics that home in on zombie cells and kill them.

By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we might be able to promote healthspan the length of time that a person is healthy, he added.

Other authors who contributed to the study were Mariarosaria de Rosa, Ph.D., Sanjana A. Thosar, M.S., Ariana C. Detwiler, M.S., Vera Roginskaya, B.S., Bennett Van Houten, Ph.D., and Jacob Stewart-Ornstein, Ph.D., all of Pitt and UPMC, and Marcel P. Bruchez, Ph.D., Carnegie Mellon University.

Funding: This research was supported by the National Institutes of Health (F32AG067710-01, K99ES033771, R35ES030396, R01CA207342 and R01EB017268), the Glenn Foundation for Medical Research, the UPMC Hillman Cancer Center Cytometry Facility (P30CA047904) and the UPMC Hillman Cancer Center Postdoctoral Fellowship for Innovative Cancer Research.

Author: Asher JonesSource: University of PittsburghContact: Asher Jones University of PittsburghImage: The image is credited to Barnes et al., Nature Structural & Molecular Biology

Original Research: Open access.Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening by Barnes et al. Nature Structural & Molecular Biology

Abstract

Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening.

Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence.

Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication.

Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

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Researchers Uncover New Pathway for Accumulation of Age-Promoting 'Zombie Cells' - Neuroscience News

Neuroscience

‘Cognitive Immobility’ When You’re Mentally Trapped in a Place From Your Past – Neuroscience News

Summary: Cognitive immobility is a form of mental entrapment that leads to conscious or unconscious efforts to recreate past instances in familiar locations.

Source: The Conversation

If you have moved from one country to another, you may have left something behind be it a relationship, a home, a feeling of safety or a sense of belonging. Because of this, you will continually reconstruct mental simulations of scenes, smells, sounds and sights from those places sometimes causing stressful feelings and anxiety.

This describes what I have dubbed cognitive immobility, outlined in my newresearch article, published in Culture & Psychology.

The study used autoethnography, a research method in which the author is also the topic of investigation. The research was partly based on my feelings, thoughts and experiences while living in the UK and Germany, far from my ancestral home in Igbo land, Africa.

Cognitive immobility is a stressful mental entrapment that leads to a conscious or unconscious effort to recreate past incidents in one or more locations that one lived in or visited in the past. By doing so, we are hoping to retrieve what is missing or left behind.

When people cannot remain in locations because of conditions beyond their control, such as a war or family or work commitments, their bodies may physically move to a new world, while their minds are left behind trapped in the previous location.

Thus, these people might be described as being cognitively immobilised. During this time, such individuals may seek consolation through the reconstruction of events or physical movement to the locations that they migrated or departed from.

This may be related to homesickness, but it is actually different. Homesickness is a feeling of longing for a previous home, whereas cognitive immobility is a cognitive mechanic that works on our attention and memory to mentally trap us in a place whether it is a previous home or just a place weve visited.

Ourconscious memory(made up of semantic and episodic memories) allows us to remember not just what happened in the past, but also basic knowledge of things around us. Specifically,episodic memoryhelps us remember or reconstruct events we experienced or events that could have happened in the past but didnt.

Indeed, research shows that recalling memory is a process of imagination we often recreate past events in a waythat isnt necessarily accurate, but rather affected by our current beliefs and emotional state. This can make our past look even better than it was.

I believe the experience may be very common for people who migrate. In an unrelatedstudy on Syrian studentswho fled to Turkey, one of them stated: I am still in Syria. My soul is there. I always have memories of my dead cousins. This affects my getting used to here.

Those days will never come back. Another Syrian student said: I left my homeland, my nation, my relatives, everything in Syria. I was physically here, but spiritually there. Both students are clearly suffering from cognitive immobility.

Due to cognitive immobility, some people who have moved from their homes to new locations perpetually long to visit their old homes. But cognitive immobility still applies when they do visit their old home, they immediately long to return to their new homeland.

So, according to my research, a person who has migrated may have a homeless mind while experiencing a situation where no home is truly ahome; even the previous home the ancestral home has lost its distinguishing features and allure in the real world.

It is easy to see why. Ultimately,there is no place without self and no self without place. Therefore, who we are is greatly influenced by the places we live or go and where we desire to be in the present and future.

The implications are serious. For example, it could lead toproblems integrating into a new placeand making new friends potentially making us even more trapped in the past as we dont have an engaging present to distract us. Constantly being stuck in the past could also get in the way of thinking ahead. This can have knock on effects for our wellbeing we need to focus on the past and present as well as the future to feel good.

According to my research, there are three stages of cognitive immobility. The first entails becoming aware of the stress and anxiety caused by leaving the location where the mind is entrapped. During this stage, most migrants experience a lot of uncertainty, which hinders their efforts in many aspects of their lives, including resettling, acquiring new skills such as language and making new acquaintances.

The second stage involves deliberate efforts to reclaim the lost or abandoned object, creating more tension than the first stage. Here, the person might engage in activities such as travelling to their ancestral land, reconstructing their memories and reading about the lost location. Although physical visits to sites could alleviate the stress, this could be a temporary solution.

The last phase consists of deliberate efforts to retain values and seek goals that will alleviate the loss. This approach might consist of using artefacts to symbolise the lost home, such as art or images.

It has also beenarguedthat migrants could make new homes, but also represent their memories and aspirations for example by making friends with people who come from the same place, or have the same religion. This is in fact one way to ultimately reduce the anxiety.

For now, it is evident that cognitive immobility has no perfect cure. But psychology offers some solutions which may prove to be useful, although they are yet to be investigated in the context of cognitive immobility.

For example, there arepsychological interventionsthat can help us balance our mental focus on the past, present and future. To avoid being stuck in the past and become more present focused, we can write down something we are grateful for every day. And to become more future focused, we could imagine our best possible self five years from now it worked for many people during the COVID lockdowns.

Author: Olumba E. EzenwaSource: The ConversationContact: Olumba E. Ezenwa The ConversationImage: The image is in the public domain

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Neuroscience

Cannes 2022 – The Neuroscience of Apple’s winners – AdNews

Shaun Seixas.

Dr. Shaun Seixas, Director of Research, Neuro-Insight

Apple had another successful outing at Cannes this year picking up multiple Lions across Film, Film Craft, Entertainment and Media categories. Two of its short form films, Detectives and Fumble are particularly noteworthy, because both the brand and product are woven seamlessly into the narrative.

How we did it

Neuro-Insight measured brain activity to see how over 100 typical viewers respond to the ad. The specific technology used by Neuro-Insight is founded in work originally developed for academic and neuroscience research and has been used to analyse the effectiveness of Cannes award winners for over eight years.

The technology allows us to simultaneously record viewers second-by-second changes in approach (like)/withdraw (dislike), emotional intensity, engagement and memory, whilst watching advertisements. Of these measures, Neuro-Insight predominantly focuses on Long-term Memory Encoding, given its strong and highly researched link to consumer behaviour. This measure reveals, second-by-second, what the brain is storing (or encoding) into conscious and subconscious long-term memory.

True Detective?

Apples aptly named Detectives spot plays on the police detective trope, with protagonist and background character waiting patiently during a stakeout. It is the early moments where the background character experiences an existential crisis about being out of focus while his foreground, in-focus partner, assures him that it is because the camera only focuses on the most important character. As the narrative plays out, the viewer is brought on a journey that plays on dramatic pauses and a big reveal, both of which are aimed to elicit a strong response in viewers.

To precisely identify the size and shape of this response we focussed on our Memory Encoding & Engagement measures to highlight the moments that strongly resonated with viewers. Memory Encoding is a strong predictor of future behaviour, contributes to creation and updating of memory structures, and is a prerequisite for mental availability. In contrast, Engagement refers to personal relevance the more relevant something is to you, the higher the levels of engagement you will experience.

Below is the times series analysis for Apples Detective spot. The red trace reflects memory encoding from the left hemisphere, which is primarily responsible for the encoding of the detail in experiences, such as text, dialogue or micro features. In contrast, the right hemisphere, reflected by the blue line, is concerned with the storing of global features, such as soundtracks, scenery, and facial expressions, as well as the emotional underpinnings of a particular experience.

We can see that the peaks of Memory Encoding & Engagement are aligned with pivotal moments in the narrative, from the early existential crisis to the threat of the big reveal, to final moments to when the background character briefly comes into focus. Whilst the actors performance, framing and screenplay each play a significant role in the strong response we see, the fact that this scene is reminiscent of many popular police procedural dramas also influences why many of these scenes were so strongly encoded and highly engaging.

Importantly, the product reveal section of the ad is also strongly encoded. Given the ubiquitous nature of the iPhone, the three camera eyes are easily recognisable and serve as another moment of branding before the Apple logo appears on screen.

A big fumble

While the pacing and tone of Detectives was slow and dramatic, Apples Fumble spot was its antithesis. Featuring a woman who is frantically trying to catch her iPhone as it fumbles from her grasp, the narrative is carried by exaggerated movements and slow motion via the rhythmic sounds of Nitin Sawhney.

Despite differences in executive when compared to Detectives, the broad shape of the memory encoding response to Fumble is similar. In particular, the ad starts strongly, with the initial fumble and soundtrack both contributing to early peak responses. This is followed by another peak in response, during the moment where we think the iPhone has been saved, only for it to be lost again. These strong responses contribute heavily to the peak responses that we observe when the main message is delivered and are sustained through to final branding.

Perhaps, the most unique feature of this spot was its ability to also connect with the viewer emotionally.

As we can see in the above graphs, the emotional response closely mirrors the different stages of the iPhone flight. The emotional response is positive during the early stages where we see the exaggerated attempt to catch the iPhone in combination with the soundtracks staccato. However, the emotional response switches to a strong level of withdraw when the phone is fumbled for the last time, and we see the pain in the protagonists face and as the phone slips away a feeling Im sure many of us have experienced. This pattern of response is indicative of anxiety, and given the current state of the iPhone, is unsurprising. Lastly, during the reveal where we see the phone is OK and a smile on our protagonists face, the emotional response switches back to positive. This response tells us the creative was successful in creating an emotional connection with the viewer; something which is quite difficult to do in a 30-second spot.

Great ads but

Youve probably heard that phrase Great ad.but who was it for? and may have even experienced it before. You see, our brain is constantly breaking up our daily experiences into smaller chunks, which form the basis for what is stored and remembered. In terms of advertising, the gaps in memory often occur as the doorway to memory is temporarily shut during final branding, a process known as Conceptual Closure. This phenomenon is highlighted in the recently published analysis of Samsungs award-winning Spider and the Window spot.

However, in the case of both Apple ads we see the opposite strong levels of memory encoding during the reveal, and importantly at final branding. Given the strong memory encoding response that we observe during the narratives of both ads, the resulting memory structures will be strongly linked to the Apple brand and further furnish the Apples brand room.

The Brand Room

The brand room is a helpful analogy for the neural networks that we create in response to brand messaging. Consider Apple as a room in the brain, which begins life bare and unacknowledged. Over time, and through repeated interactions with the brand, the room becomes furnished with opinions, colour, and memories of the brand and its associations.

Putting it all together

Apple has been consistently active during the pandemic with various campaigns that either spoke to the quality of video on the iPhone (Shot on iPhone series) or highlighted other iPhone features. These two ads which were part of those campaigns were highly effective from a neuroscience standpoint and undoubtedly contributed to Apples bottom line. In particular, Apple increased its hold on premium phone sales from 57% in Q1 2021 to 62% in Q1 of 2022. Given how well Apple campaigns have performed over the past year and consistently being in front of potential new customers, it comes as no surprise that the brand continues to grow at the expense of competitors.

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Neuroscience

When ASD Occurs With Intellectual Disability, a Convergent Mechanism for Two Top-Ranking Risk Genes May Be the Cause – Neuroscience News

Summary: Mutations in the ASD/intellectual disability genes ADNP and POGZ result in abnormal activation and overexpression of immune response genes and genes for microglia. This results in abnormal brain synaptic function, characteristic of ASD and ID.

Source: University at Buffalo

University at Buffalo scientists have discovered a convergent mechanism that may be responsible for how two top-ranked genetic risk factors for autism spectrum disorder/intellectual disability (ASD/ID) lead to these neurodevelopmental disorders.

While ASD is distinct from ID, a significant proportionapproximately 31%of people with ASD also exhibit ID. Neither condition is well-understood at the molecular level.

Given the vast number of genes known to be involved in ASD/ID and the many potential mechanisms contributing to the disorders, it is exciting to find a shared process between two different genes at the molecular level that could be underlying thebehavioral changes, said Megan Conrow-Graham, Ph.D., first author and an MD/Ph.D. candidate in the Jacobs School of Medicine and Biomedical Sciences at UB.

Published today in the journalBrain, the paper focuses on ADNP and POGZ, the two top-ranked risk factor genes for ASD/ID. The research demonstrates that mutations in these genes result in abnormal activation and overexpression of immune response genes and genes for a type of immune cell in the brain called microglia.

Our finding opens the possibility of targeting microglia and immune genes for treating ASD/ID, but much remains to be studied, given the heterogeneity and complexity of these brain disorders, said Zhen Yan, Ph.D., senior author and SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School.

The UB scientists found that mutations in the two genes studied activate microglia and cause immune genes in the brain to be overexpressed. The hypothesized result is the abnormal function of synapses in the brain, a characteristic of ASD/ID.

The research involved studies on postmortem brain tissue from humans with ASD/ID, as well as studies on mice in which ADNP and POGZ were silenced through viral delivery of small interference RNA. These mice exhibited impaired cognitive task performance, such as spatial memory, object recognition memory and long-term memory.

Weakening a repressive function

Under normal conditions, cells in the central nervous system should not express large quantities of genes that activate the immune system, said Conrow-Graham.

ADNP and POGZ both work to repress these genes so that inflammatory pathways are not continuously activated, which could damage surrounding cells. When that repression is weakened, these immune and inflammatory genes are then able to be expressed in large quantities.

The upregulated genes in the mouseprefrontal cortexcaused by the deficiencies in ADNP or POGZ activated the pro-inflammatory response.

This is consistent with what we see in upregulated genes in the prefrontal cortex of humans with ASD/ID, said Conrow-Graham. The prefrontal cortex is the part of the brain responsible for executive function, such as cognition and emotional control.

The mutated genes also activate the glial cells in the brain called microglia, which serve as support cells for neurons and have an immune function in the brain; they comprise 10-15% of all brain cells.

Sensitive microglia

Microglia are very sensitive to pathological changes in the central nervous system and are the main form of active immune defense to maintain brain health, explained Yan. Aberrant activation of microglia, which we demonstrate occurs as a result of deficiency in ADNP or POGZ, could lead to the damage and loss of synapses and neurons.

The researchers are hopeful that future research will determine whether chronic neuroinflammation could be directly contributing to at least some cases of ASD/ID, in which targeting microglia or inflammatory signaling pathways could prove to be a useful treatment.

The researchers pointed out that the clinical presentation of both ASD and ID is incredibly varied. Significant variation also likely is present in the kinds of mechanisms responsible for the symptoms of ASD and/or ID.

We found that changes in two riskgeneslead to a convergent mechanism, likely involving immune activation, said Conrow-Graham. However, this probably isnt the case for all individuals with ASD/ID. When designingclinical trialsto evaluate treatment effectiveness, I think our research underscores the importance of considering the genetic factors involved in an individuals ASD/ID.

The research is the culmination of Conrow-Grahams Ph.D. work; she has now returned to complete the last two years of the MD degree in the Jacobs School. She described her experience pursuing both an MD and a Ph.D. as extremely complementary.

The immune system has a role

My training at each level was super helpful to supplement the other, she said. When I began my Ph.D., I had completed two years of MD training, so I was familiar with the basics of physiology, anatomy and pathology.

Because of this, I was able to bring a broader perspective to my neuroscience research, identifying how the immune system might be playing a role. Prior to this, our lab had not really investigated immunology-related pathways, so having that background insight was really beneficial.

She added that she learned so much from all of her colleagues in Yans lab, including faculty members, lab technicians and other students. I learned so many technical skills that I had never used before joining the lab, thanks to the dedication of lab co-workers for my training, she said.

Her experience at the lab bench working on the basic science underlying neuropsychiatric disorders will definitely influence her work as a clinician.

I plan to pursue a career as a child and adolescent psychiatrist, so I may be able to work directly with this patient population, she said.

Were learning now that better care may be able to be provided by taking a personalized medicine approach, taking into account genetics, psychosocial factors and others. Being able to take a very deep dive into the field of psychiatric genetics was a privilege that I hope will help me to provide the best care for patients.

Author: Ellen GoldbaumSource: University at BuffaloContact: Ellen Goldbaum University at BuffaloImage: The image is in the public domain

Original Research: Closed access.A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders by Megan Conrow-Graham et al. Brain

Abstract

A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders

ADNPandPOGZare two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. BothADNPandPOGZare chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain.

Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression ofADNPandPOGZin the prefrontal cortex, a region highly implicated in neurodevelopmental disorders.

To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate howAdnporPogzdeficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency ofAdnporPogzexhibited specific impairment of cognitive task performance.

RNA-sequencing revealed thatAdnporPogzdeficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly,AdnporPogzdeficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression.

These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.

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Embryology

How Does Comparative Embryology Support the Theory of Evolution?

Comparative embryology supports the theory of evolution because scientists have found that the embryos of many different species show similarities, which implies they share a common origin. For example, in humans the embryo passes through a stage in which it has a gill structure similar to that of fish. Human embryos also have a tail, much like other primates, though the tail is usually re-absorbed before birth, and this suggests that, even though their adult forms are different, these various species all have a common ancestor.

Furthermore, the embryo serves as a microcosm for evolution. The embryo passes through many stages of evolution until it finally reaches its adult form.

While the appearance of ancestral traits in the embryos of many organisms is well documented and can provide insights into the evolution of a species, an early attempt to draw direct parallels between the development of an embryo (ontogeny) and the development of its species (phylogeny), known as the Recapitulation Theory, is widely believed to have been discredited by later science.

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Embryology

Widower wins right to have baby using embryo created with his late wife – The Guardian

A 38-year-old widower has won a landmark legal case giving him the right to have a baby with a surrogate using the last remaining embryo created with his late wife.

Ted Jennings and his wife, Fern-Marie Choya, had spent years trying to have children and had sought fertility treatment, but Choya died suddenly while pregnant with twin girls in 2019. The fertility regulator, the Human Fertilisation and Embryology Authority (HFEA), rejected Jenningss request to be able to use their last frozen embryo to start a family because Choya had not given written consent for posthumous surrogacy.

But on Wednesday, the high courts family division ruled that Jennings can use the embryo, in what could be the UKs first case of posthumous surrogacy. The couple had not been given adequate opportunity to consent to this scenario, the court found, in a judgment that will put pressure on the HFEA to review consent procedures.

In her judgment, Mrs Justice Theis, a family division judge, said: I am satisfied that, in the circumstances of this case, the court can infer from all the available evidence that Ms Choya would have consented to Mr Jennings being able to use their partner-created embryo in treatment with a surrogate in the event of her death. This is being considered in the context where, in my judgment, she had not been given relevant information and/or a sufficient opportunity to discuss it with the clinic.

The couple, both originally from Trinidad, met in London and married in 2009. After five years of fertility treatment and two miscarriages following ectopic pregnancies, they conceived in 2018 and were expecting twin girls. But 18 weeks into her pregnancy, Choya suffered a severe pregnancy complication and died, aged 40.

The couple had given consent to the embryos being used in the event of Jenningss death, the court heart in evidence last month, but Choya was not asked the equivalent question. Instead, her form stated that she should seek more information from the clinic if you wish your eggs or embryos to be used in someone elses treatment if you die. The court ruled that it was far from clear how this related to posthumous surrogacy and suggested that the HFEA may want to consider whether the form should be reviewed in order to provide the clarity required and avoid this situation occurring again.

James Lawford Davies, Jenningss lawyer and a partner at the firm Hill Dickinson, said: I am delighted that the court has found in Teds favour and that he can now proceed with surrogacy treatment. It was clear that this is what Fern would have wanted and this very thorough judgment allows her wishes to be respected.

In a statement, the HFEA said: This is a tragic case and the HFEA continues to have every sympathy for Mr Jennings. The act of parliament which governs fertility and embryology in the UK is clear that signed written consent is always required in such cases. The risk today is that this decision will undermine that position, and diminish the protection it gives to a persons express wishes about the use of their embryos after their death. We will carefully consider the judgment before deciding whether to appeal.

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Widower wins right to have baby using embryo created with his late wife - The Guardian

Embryology

The End of the Beginning of the End of Abortion | Hadley Arkes – First Things

The decision today in the Dobbs case, long awaited from the Court, can be appreciatedand savoredas a resounding first step. To rephrase Churchills line, we might say that we are only at the end of the beginning in dealing with the turbulence that abortion has imparted to our political life for the past fifty years. That turbulence promises to rise now to new levels of enmity, until our people can regain some moral clarity on the taking of innocent life in the womb. But something good has been done, and there is an analogy here to the Emancipation Proclamation:It freed only the slaves held in states at war with the national government;it did not free slaves held in border states such as Delaware.And yet it became clear that it was animated by an anti-slavery impulse, and thats how it came to be understood.In the same way, this decision will be seen as a decision affirming life. It will be seen as inviting legislatures in the states to begin casting the protections of the law over the unborn child in the womband it will do that even though the conservative majority goes out of its way to avoid any such invitation or encouragement.

Still, the decision will be seen as a pro-life proclamation even as abortions proceed at a massive level in the blue states.Our disappointment here mirrors that of people on the other side:They are feeling dispossessed, because they thought they bore nothing less than a constitutional right, which does not go in and out of effect when they move from one state to another. And for our part, we lament the fact that the Court does not move to put the critical anchoring point in place as it sends the matter back to the states: Namely, that as we draw on the objective facts of embryology, that offspring in the womb has never been anything less than human from its first moments, and not merely a part of the mother. If that predicate were put in place, there would be a clearer understanding of what makes it deeply justified for the laws in the states to cast their protections over the child in the womb. And what makes it warranted in turn for Congress and the federal courts to act when the protections of the law are withdrawn from a whole class of human beings in the states.

But the majority in Dobbs conspicuously held back from putting that premise into place. And that is why the dissenting opinion by Justice Stephen Breyer makes no contact with the opinion he is ostensibly opposing. Breyer charges that the Court today says that from the very moment of fertilization, a woman has no rights to speak of. A State can force her to bring a pregnancy to term, even at the steepest personal and familial costs. And yet that is what Justice Samuel Alito and his colleagues sought carefully to avoid saying. The issue of abortion has been returned to the states, and the Court has offered no directions as to how and when a legislature may choose to protect the child in the womb. The Court has simply decided that nothing in the text of the Constitution, or the legal history of this country, has ever recognized such a right to abortion. As one of my own friends among the justices once put it:

The matter will be sent back to the states and people will be invited to reach their own judgment on how much they value the life of the fetus in the womb. The dissenters take it as a given that the only persons with serious interests at stake here are the women who see their lives and prospects diminished if they are deprived of the chance to order an abortion at a timely moment. What is notably erased from the screen is any recognition of that small creature in the womb, as one who might have the standing of a human being, and whose injuries count.

What the dissenters pretend not to see is that the conservative majority in Dobbs has done nothing to refute that assumption. It has not moved to put in place the rival understanding that the child is indeed a human being with a claim to be protected by the law from its first moments. Justice Alito was quite crisp in pointing out that the test of viability made little sense here. Whether a child sprung from the womb has a decent chance of being sustained outside the womb may be an interesting question in incubator science, but it has no bearing on whether the child has ceased being anything other than a human being at any stages of the pregnancy. Alito came the closest, though, to insisting on that claim of the child to the protection of the law even at its earliest moment: The legitimate interests of the state in regulating abortion could tenably encompass, as he said, a respect for and preservation of prenatal life at all stages of development. But he evidently felt constrained from saying what James Wilson said in the first days of the Constitution. Wilson, one of the premier minds among the American founders, asked this question: If we have natural rights, when do they begin? And his answer was: They begin as soon as we begin to be. And so as he wrote:

For all we can tell, that sense of things was decisively rejected by Alitos colleague Justice Brett Kavanaugh in his morally curious claim that the Constitution is neutral on abortion: On the one side, he wrote, many pro-choice advocates forcefully argue that the ability to obtain an abortion is critically important for womens personal and professional lives, and for womens health. . . . On the other side, many pro-life advocates forcefully argue that a fetus is a human life. In other words, on this construction, a conservative jurisprudence on abortion must begin with the axiom that there is no truth to be known on the human standing of that child in the womb. But that is a jurisprudence that accepts, as its grounding, a radical falsehood. Whatever else it is, it cannot be a coherent jurisprudence.

Justice Kavanaugh is a thoughtful man, and some of us hope that he is willing to take a sober, second look at what he has put in place here. He catches the sense of the holding here: The Court will pronounce no truth on the human standing of that child in the womb, nothing that must provide the predicate for anything that will be legislated in the states. This grave matter, returned to the states, will be argued over in the domain of beliefs and value judgments, with no fixed truths on when human life begins. But in that case, we should not be surprised to discover people in the pro-life states complaining that they have been dispossessed of a deep personal right simply because it wasnt supported by the opinions and beliefs of 51 percent of the people around them.

It is a good thing that this first step has been taken, and the paths of persuasion and argument have opened again. There can be no question that the Court, over the past fifty years, has been the chief engine in changing the culture of this country on abortion. It did not merely pronounce a legal judgment; it tutored the country on the moral rightness of abortion, and the rightful sense of grievance for anyone deprived of that right. And so it becomes apt to ask just what rival teaching the Court will be putting in place now for our people as it sends the matter back to the states. We can be grateful for the decision in Dobbs, but if the American people come to absorb now the notion that the standing of human life bears no objective truth, that the respect for that life depends on the vagaries of opinions whirling aroundus, we can earnestly wonder how the Court is reshaping for the better the sensibilities of people who will be filling this landscape all around us.

And so again, this is the end of the beginning, and now the work begins anew.

Hadley Arkes is the Ney Professor of Jurisprudence Emeritus at Amherst College and the Founder/Director of the James Wilson Institute on Natural Rights & the American Founding in Washington, D.C.

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The End of the Beginning of the End of Abortion | Hadley Arkes - First Things

Embryology

Harry Potter’s World Similar to the Magic of Endocrinology – Medscape

Clinicians don't cease diagnosing patients once our clinical work is done. Most of us can recall debating whether to point out an atypical mole or another concerning finding to a stranger in public.

Like the doctor back in 2018, who saw a lump on the neck of a woman on TV and reached out via a video on Facebook, which found its way to her. She was eventually diagnosed with thyroid cancer.

Patients even recognize their own experiences and help lead others to clinical care.

And our diagnostic abilities can sometimes prove entertaining when interpreting plotlines in all sorts of storytelling, with endocrinology often making appearances in literature and film.

For instance, much debate has ensued about what Tiny Tim probably suffered from in Dickens's A Christmas Carol; a combination of tuberculosis and rickets makes the most sense to me, as detailed in a report in JAMA.

Malcolm Gladwell pointed out that Goliath in the biblical story probably got his stature and his inability to miss a shepherd boy's slingshot from a pituitary tumor. And the plot of Steel Magnolias revolves around type 1 diabetes.

Most recently, I began to see endocrinology everywhere in probably the most successful series of stories of recent times: the Harry Potter chronicles.

If, like me, you have a Potter-obsessed household, you might have watched the Return to Hogwarts special on HBO earlier this year. One of the observations that piqued my attention was when Emma Watson and Daniel Radcliffe joked about the hormones running rampant as the characters and actors who played them navigated adolescence, growing from children to teens as they made successive movies.

Popular culture has picked up on the comedy of these sometimes awkward pubertal transitions, repeatedly skewered by Saturday Night Live. However, this line made me ponder other less-famous hormones that could explain some of the fantastical findings of the wizarding world.

Hormones invisible chemical messenger are truly magical. They are most famous for sexual development but also empower growth, bone strength, fluid homeostasis, weight, carbohydrate metabolism, salt balance, blood pressure regulation, and any other function you can imagine; indeed, thyroid hormone is crucial for almost every system of the body.

Perhaps, the notable transformation of the main characters through puberty isn't the only hormonal influence we should credit. (This article may contain spoilers: My husband didn't read the Harry Potter series until we read it to our second grader so sadly learned at the age of 37 about the tragedy that befell Dumbledore.)

Just for fun, here are some other hormonal diagnoses that could explain some of the dark arts represented in the series.

Could Hagrid the giant have acromegaly? Clinical signs include enlarged hands and feet as well as excess growth of the ears and nose. A good way to check for these changes is to compare old photographs with the present condition. The actor who plays Hagrid, Robbie Coltrane, looks very different from the character after his transformation. Someone check his IGF-1 the hormone that manages the effects of growth hormone!

Neville Longbottom, the series' late bloomer, is the poster child for teens with constitutional delay of growth and puberty. This often frustrating but benign condition that plagues the "slow developer" tends to run in families and causes those who have it consternation as they wait to grow while their peers surpass them in stature and other ways; it also leads for them to be underestimated, as we witness with Neville in the Harry Potter series.

Voldemort: Depicted without a nose, if He-Who-Must-Not-Be-Named had congenital central abnormalities, he should be screened for central pituitary hormone deficits because the pituitary gland shares common embryology with other midline structures. (His evil has nothing to do with his possible underlying endocrinopathies.)

The Weasley family: if any of these redheaded wizards presented with adrenal insufficiency and rapidly progressive obesity, a POMC (proopiomelanocortin) mutation should be considered.

Nearly Headless Nick's near-decapitation might have affected his thyroid or parathyroid glands Hogwarts physician Madame Pomfrey should pay special attention to his thyroid stimulating hormone and calcium levels, at least if she is willing to take advantage of Muggle remedies.

Moaning Myrtle, who was killed by the Basilisk in the girls' lavatory, continues with tantrums and moans as she haunts the same bathroom at Hogwarts. Could it be that Myrtle's groans and psychiatric overtones were a sign of hypercalcemia, and she was using the facilities as she tried to pass a kidney stone? At the very least causes of polyuria should be investigated, including diabetes insipidus and diabetes mellitus. A unifying diagnosis of never being able to leave the bathroom and vision changes requiring serious glasses like hers would be untreated septo-optic dysplasia or other causes of pituitary malformation or disruption.

And though Dolores Umbridge doesn't have an obvious endocrine disorder, she seems like the kind of person who would visit an endocrine office after doing loads of "her own research" and arrive with a list of labs she demands.

Severus Snape provides a good opportunity to point out someone with excessively greasy skin and abnormal sweating (hyperhidrosis) as an adult, symptoms that perhaps would be best managed by our colleagues in dermatology.

The Dementors: These demons clearly work for insurance companies, tormenting the young wizards with denials and prior authorization requests.

Enzyme names sound a lot like spell incantations. Iodothyronine deiodinase? HMG CoA reductase? Future authors looking for new spells need look no further than their closest endocrine textbook.

Please note, I consider all my patients to be miraculous and worthy of admiration these comparisons are all in good fun and in no way diminish the weight of these conditions.

As Rubeus Hagrid himself said, "I am what I am, an' I'm not ashamed. 'Never be ashamed,' my ol' dad used ter say, 'there's some who'll hold it against you, but they're not worth botherin' with.'"

Like magic, endocrinology can't be seen with the naked eye, but it's everywhere we look, if only we choose to look.

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Harry Potter's World Similar to the Magic of Endocrinology - Medscape