Researchers Identify Why Some Cancers Do Not Respond to Immunotherapy – NYU Langone Health

Over the last decade, immune checkpoint blockade has transformed cancer care by offering new hope and improved outcomes for people with certain types of cancer. However, immune checkpoint blockade, a type of cancer immunotherapy that enhances the bodys natural immune response against tumor cells, is only effective in 20 to 30 percent of patients with cancer. And people with some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance to the immunotherapy.

A recent study by researchers at NYU Langone Healths Perlmutter Cancer Center could lead to new strategies for improving the effectiveness of immune checkpoint inhibitors. The researchers identified an axis or pathway that tumor cells use to shut down the function of a key molecule called major histocompatibility complex (MHC) class I. Under normal conditions, MHC class I enables the immune system to detect and eliminate cells that have been transformed or infected.

Study senior co-author Jun Wang, PhD, a cancer immunologist, has a background in viral immunology. Through his earlier studies of viruses and the immune system, he knew that viruses are able to shut down MHC class I to evade T cell response. What if, he asked, cancer cells can do the same?

We know that viruses can very efficiently shut down MHC class I and evade the immune system, said Dr. Wang, who is an assistant professor in the Department of Pathology at NYU Grossman School of Medicine. How tumors can shut down MHC class I has not been clear at all.

The immune system recognizes and eliminates infected or mutated cells through a process called antigen presentation. During antigen presentation, intracellular pathogens, such as viruses and certain bacteria, or abnormal cellular proteins, such as those from cancer cells, are transported by MHC class I molecules and presented to killer T cells, which are activated and mount an immune response.

With study senior co-author Iannis Aifantis, PhD, and co-first authors Xufeng Chen, PhD (Aifantis Lab), and Qiao Lu, PhD (Wang Lab), Dr. Wang used a gene editing technology called CRISPR to screen for new cellular activators and inhibitors of antigen presentation in AML. Among the top hits in the CRISPR screen were three proteins: sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and an E3 ubiquitin ligase WWP2. The researchers found that SUSD6 forms a trimolecular complex with TMEM127 and MHC class I, which recruits WWP2 to initiate the degradation of MHC class I and ultimately leads to suppression of MHC class I expression.

When the researchers deactivated SUSD6, which is abundantly expressed in AML and several other solid cancers, antigen presentation by MHC class I was improved and tumor growth was reduced in cell cultures.

We were able to show that if we genetically target this particular complex, we boost the expression of MHC class I with more antigen on the surface and have better recognition by T cells, said Dr. Aifantis, who is the Hermann M. Biggs Professor of Pathology in and chair of the Department of Pathology at NYU Grossman School of Medicine.

Immune checkpoint inhibitors have been particularly ineffective against cold tumors, which do not attract large numbers of immune cells. The trimolecular complex Dr. Wang and his colleagues identified is highly expressed on cold tumors, which suggests that the complex, in addition to being a new target for developing antibodies or small molecules that block its function, could act as a biomarker to help predict which patients will benefit from immunotherapy.

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Researchers Identify Why Some Cancers Do Not Respond to Immunotherapy - NYU Langone Health

Physician and Patient (Un)Wellness in Allergy and Immunology During COVID-19 and Beyond: Lessons for the Future – Physician’s Weekly

The following is a summary of Allergy and Immunology Physician and Patient (Un)Wellness During COVID-19 and Beyond: Lessons for the Future, published in the November 2023 issue of Allergy and Clinical Immunology by Bingemann, et al.

The COVID-19 outbreak made both patients and doctors more stressed and less healthy. Uncertainty, regular changes, fear of getting sick or dying, and problems with the supply chain put extra stress on a healthcare system that was already broken. Control, regularity, and confidence make for a good workplace. The outbreak took away these things. During this time, the number of depressed, suicidal, and anxious doctors and people in the general population went up. These problems got worse because people had different ideas about masks and vaccines.

These things, along with how much people felt appreciated or not, also made stress worse. Some changes, like switching to video, were stressful initially, but they made patients happy and kept clinical care going. Some changes could have been better, like teaching or watching young children while working. Both patients and doctors did their best to deal with loneliness, fear, worry, and the many changes in society. During the pandemic, burnout changed depending on the number of infections, the number of vaccinations, problems with the supply chain, and the amount of support given to each person.

The pandemic brought to light problems in their healthcare system, such as structural racism, differences in healthcare, and how quickly the system can become overloaded. Doctors may have been put in positions they didnt want to be in or may need more staff to practice how they wanted. Patients and doctors both got angry because of these things. In its National Plan for Health Workforce Well-Being, the government says that health care needs to be reformed so that patients can get good, safe care and doctors dont get burned out.

Source: sciencedirect.com/science/article/abs/pii/S2213219823009273

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Physician and Patient (Un)Wellness in Allergy and Immunology During COVID-19 and Beyond: Lessons for the Future - Physician's Weekly

MU’s Haval Shirwan recognized for achievements in immunology – Columbia Daily Tribune

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MU's Haval Shirwan recognized for achievements in immunology - Columbia Daily Tribune

Comparing characteristics and perspectives of U.S. anesthesiology fellows in training and anesthesiologists in their first … – BMC Medical Education

A career in anesthesiology provides an opportunity for a varied, stimulating and fulfilling practice and has been popular as a specialty choice for graduating medical school students in the U.S. and elsewhere [11]. Residents in anesthesiology report satisfaction with their training [8], and many experienced anesthesiologists remain enthusiastically engaged in their work. Nevertheless, the profession of anesthesiology faces challenges and our survey study evaluated the perceptions of first-year graduates of U.S. anesthesiology residencies on this issue. The main finding was that these early career anesthesiologists perceived challenges fell into three broad themes - workforce competition from non-physician anesthesia providers and unease about external perception of anesthesiologist value, changes in the healthcare system that led to concerns about lower compensation and threats to patient care, and personal stressors including disquiet over burnout and the need to meet professional standards. These results highlight issues for programs and organizations to address. The perceived challenge to employment security posed by CRNAs and the perceived lack of appreciation for anesthesiologist value were most frequently cited. Although both AFs and DEs had similar concerns about the profession of anesthesiology, the relative weighting of their worries was different and may be the reasons behind or a consequence of their decision to pursue or not pursue a fellowship.

Demographic characteristics of AFs and DEs were similar and reflective of the life-stage of typical North American residency graduates. The influence of family factors on the decision to enter fellowship has previously been documented by Khan et al. among Canadian anesthesiology residents [6]. Having children may be a disincentive to fellowship because of the work hours involved, on-call responsibilities, and the unpredictability of these responsibilities. We suggest that implementation of measures to make fellowships more accommodating to anesthesiologists with, or intending to have, children would encourage more residents to consider that path [12]. Such measures might include enhancement of schedule flexibility, more accommodating leave-of-absence policies, support for nursing mothers, and improved access to childcare [13,14,15]. A greater amount of educational debt decreases the likelihood of a physician selecting a post-residency academic position and increases residency graduates interest in anesthesiology groups with an educational debt repayment program [3, 16, 17]. Although student debt was not reported as a major challenge in this study and debt burden was similar among AFs and DEs, those who chose to go directly into independent practice were slightly older, had more dependents, and were more likely to have a spouse who did not work outside the home, factors that may have influenced a perceived imperative to achieve financial security for their families. Although statistically significant, these differences were modest, and it is not clear that such modest differences would be determinative in making such an important life decision. Consistent with previous reports [7], a substantial proportion of respondents were not satisifed with their personal and professional life balance, although DEs expressed greater satisfaction than AFs.

From the perspective of U.S. anesthesiology residency graduates, the greatest challenge to the profession of anesthesiology identified from free-text comments was competition from non-physician anesthesia providers, the subject of more than half of all comments. This level of concern does not appear to be a new phenomenon [18, 19], but its persistence is striking. Of interest, compared to when these cohorts were CA-3 residents [2], AFs in training were slightly more concerned about this workforce competition while DEs were less concerned. We speculate that some DEs had seen first-hand how a highly functioning collaborative practice could work, whereas fellows lacked the real world experience and were apprehensive about their unknown post-fellowship employment. Providing more opportunities for fellows to participate in collaborative practice with advanced practice providers may help ease such concern and better prepare them for the care team they may lead in their future practice. Previous work has demonstrated the vulnerability and discrimination experienced by female anesthesiologists worldwide [20, 21]. Although many female DEs in our study were concerned about a perceived lack of differentiation between anesthesiologists and CRNAs (approximately 60% of CRNAs are female) [22], the proportion relative to other groups was not statistically significant. It was notable that those DEs who practiced predominantly in the care team model in a large practice (i.e., infrequently or never personally administered anesthesia as the sole provider) were more likely to raise a concern about the external perception of anesthesiologist value and a perceived lack of advocacy for the profession [23, 24]. To alleviate the concern, professional organizations and major hospitals could use diverse platforms and channels, including participation in medical conferences, strategic engagement on social media, and featured content in healthcare publications, to spotlight the contributions and expertise of anesthesiologists and foster a broader understanding and appreciation of their role in healthcare.

The choice of fellowship influenced the perception of competition from non-physician anesthesia providers. Advanced training was seen by some as a means to further differentiate anesthesiologists from non-physicians. Subspecialty training in either critical care medicine or cardiac anesthesiology was associated with a lower concern about workforce competition. Critical care medicine practice seems to be sufficiently different from operating room anesthesia that fellows feel assured that their physician subspecialty skills are more difficult to replace. Indeed, we previously documented that anesthesiology residents considered their critical care rotation as one of the most important rotations in clinical anesthesia training [8]. Although nurse practitioners increasingly deliver care in intensive care units, such individuals are usually not CRNAs. We also postulate that the routine integration of echocardiography training into cardiac anesthesiology fellowship helps differentiate the role of the cardiac anesthesiologists from that of the cardiac operating room CRNAs, which results in a decrease in the competition concern. Less easily explained, however, is that pain medicine fellows had the highest concern about workforce competition. Perhaps an explanation lies in the increasing number of non-anesthesiologist physicians and non-physicians who provide care in pain management [25, 26] in the U.S. and thus a heightened sensitivity to this issue among anesthesiology pain medicine fellows and consultants.

Within the second identified theme of healthcare system changes, concerns relating to financial compensation were most prominent. Many responses included specific concerns about decreasing reimbursements and bundled payments. Although female anesthesiologists salaries are 512% lower than those of male anesthesiologists [27] and female anesthesiologists face inequity in clinical practice [28], it was the male respondents in our cohort who were more likely to express concerns about compensation. DEs in large practices who often or exclusively perform their own cases were especially concerned about their renumeration. We speculate that their lack of a multi-room supervisory practice made these anesthesiologists feel vulnerable to identification as an in-room provider, similar to a CRNA or AA, with subsequent concern that they would be compensated at lower rates than those anesthesiologists whose practice model allows them to bill for simultaneous cases. Finally, our data, analyzed according to four U.S. regions of respondent practice location, demonstrated that compared to DEs in the northeastern region, those in the Southeast and West were more concerned about compensation. This may be partly due to regional differences in the anesthesiology workforce and the location-specific ratio of CRNAs to anesthesiologists [29, 30]. Although anesthesiologists are well compensated, our findings suggest that financial challenges are of significant concern at the outset of a career in the profession.

Although respondents had free range to identify any perceived challenges to the profession and to them, it is reassuring and concerning - that primacy of patient welfare was highlighted as the principal challenge by about 8% of respondents. Threats to patient care were identified especially by those in the high acuity subspecialty of cardiac anesthesiology and those in large- and medium-sized groups who frequently or exclusively performed their own cases. One could speculate that this may be reflective of concerns held by those anesthesiologists who are routinely charged with caring for the most complex cases in what they perceive are increasingly corporate systems that prioritize economies and efficiencies.

The findings of our report are consistent with data obtained from senior anesthesiology residents as part of the ABA sequential cross-sectional survey study [2]. Similar themes were identified in that cohort, with work force competition from non-physician anesthesia providers being perceived as the greatest threat to the profession, followed by changes in the healthcare system and personal challenges. AFs, DEs, and senior anesthesiology residents were similarly concerned with undervaluation of anesthesiologists by others and lack of advocacy for physician values, an advocacy role more prominent than in any other medical specialty in the U.S.

As we have discussed in previous publications, our analyses based on repeated cross-sectional surveys are subject to limitations [2, 7, 8]. Of special relevance to the evaluation of perceived challenges to the profession was the potential for respondent bias, possible sources of which include subjective views of themselves, their practice, or the profession, and a deliberate portrayal of a specific view to the ABA. For example, respondents may have been reluctant to talk about their own compensation, but more willing to raise concerns about undervaluation of anesthesiologists. Additionally, although we strived to follow best practices of data collection and analysis, the free-text responses were open to interpretation, especially those that were brief and did not elaborate on the context. Our methodology allowed measurement of the frequency with which concerns were spontaneously expressed but not the prevalence of those concerns within the cohort. Respondents had to identify the greatest challenge facing the profession of anesthesiology; they would not likely have reported all challenges that may have been important to them. Further, our data reflect the views of U.S. anesthesiologists and were collected before the COVID-19 pandemic as part of a repeated cross-sectional study of stable cohorts, and do not reflect views of anesthesiologists outside of the U.S. or changes that may have occurred since the onset of the pandemic. Some of the post-pandemic changes in the U.S. include shortages of both anesthesiologists and CRNAs, upward compensation adjustments because of those shortages, and consolidation and increased corporatization of practices. Future studies could utilize the results of this study to make comparisons about how the challenges and perceptions have changed since the COVID-19 pandemic.

In summary, our data provide insight into the characteristics of AFs and DEs and their perception of challenges to the profession of anesthesiology in the U.S. The demographic characteristics of these two groups were largely similar. Although differences in age and family factors may suggest possible motivations for choosing fellowship or not, the importance of these small differences is uncertain. Our investigation of free-text responses to the question of the greatest challenge facing anesthesiology highlighted three major themes in descending order of frequency: workforce competition, healthcare system changes, and personal challenges. Members of the AF and DE groups shared these same concerns, but the relative weighting of these concerns was different and influenced by demographic and professional variables such as gender, fellowship subspecialty, and independent practice characteristics. These physicians represent the next generation of anesthesiologists in the U.S., who will drive the future directions of the specialty. We hope that our identification of the challenges they face and their concerns will inform advocacy and policies at programmatic and professional organizational levels.

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Comparing characteristics and perspectives of U.S. anesthesiology fellows in training and anesthesiologists in their first ... - BMC Medical Education

The Impact of a New Anesthesiology Residency Program on the Number of Medical Students Matching Into … – Cureus

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Tips from neuroscience to form healthy habits and break unhealthy ones – The Washington Post

Sharing your goal with friends to stay accountable or making a more public commitment, on social media for example, can be helpful tools for some people, Bermdez said.

Reframing the benefits of a goal can also be a powerful tool. If your goal is exercise-focused but the physical and psychological benefits arent motivation on their own, reframing time spent exercising as, Oh, this is a chance for me to catch up with my podcasts or with the music that I love, or its a chance for me to go outside, can be helpful, Bermdez said. Conversely, to break a habit, focus on the negatives of the tempting action, he said, because it will start to look increasingly less appealing.

Bermdez said its important to monitor if the strategy youve chosen is working and, if not, to be open to trying others. You may even need to reevaluate the goal itself.

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Tips from neuroscience to form healthy habits and break unhealthy ones - The Washington Post

SYNGAP1 findings illuminate links between mutations, intellectual disability – The Transmitter: Neuroscience News and Perspectives

Brain communication relies on a complex set of connections, coordinated by important synaptic proteins. Mutations in one such protein, SYNGAP1, which is critical for brain plasticity, can lead to neurodevelopmental conditions.

SYNGAP1-related intellectual disability (SRID) makes up about 1 percent of intellectual disability cases. It is characterized by seizures, developmental delays and problems with motor coordination. About half of people with SRID have autism.

Recently, a flurry of new SYNGAP1 findings and the development of novel mouse models have expanded scientific understanding of the protein and gene. Together, this work may point to multiple therapeutic possibilities for SRID.

I think its an exciting time, says Gavin Rumbaugh, professor of neuroscience at UF Scripps Biomedical Research in Jupiter, Florida. There is a lot of increased interest in SYNGAP.

For example, past research has indicated that the protein acts as an enzyme to modulate the synaptic connections between neurons. But SYNGAP1 protein may also regulate synaptic plasticity and cognition by physically controlling the number of neurotransmitter receptors at excitatory synapses, according to a preprint posted on bioRxiv in August.

Other work suggests a new role for the gene and protein. In the past, they have primarily been recognized for their effects on synapse functioning. But now SYNGAP1 joins several autism-linked genes that code for synaptic proteins that also shape the developing brain.

A mutation that decreases SYNGAP1 protein levels may exert significant effects on the development of the cortical layers in a human organoid model by disrupting the differentiation of supporting cells that serve as a scaffold for neurons to migrate during development, Rumbaugh and his colleagues have found. Their study was published in Nature Neuroscience in November.

Its very important to use model systems to test the function of the proteins associated with disease at different developmental time points and in different cell types, says lead investigator Giorgia Quadrato, assistant professor of stem cell biology and regenerative medicine at the University of South California in Los Angeles.

A

In developing human neurons cultured in a dish, a lack of SYNGAP1 leads to increased cell size and dendrite length, and speeds up the onset of synaptic activity.

But it was unclear whether or how small mutations in the gene the situation typically seen in people with SRID affect the levels and function of the SYNGAP1 protein, synaptic plasticity and behavior in animals. To address this, lead investigator Richard Huganir and his team at Johns Hopkins University in Baltimore, Maryland, developed two new mouse models.

Each model is based on mutations in the SYNGAP1 gene as they appear in two people a young boy and girl. Its much better to have [models] with patient-based mutations for future therapeutics, says Huganir, professor of neuroscience.

Using CRISPR, the group introduced the two faulty versions of SYNGAP1 into different sets of healthy mice. Both mutations reduced SYNGAP1 protein levels by about 50 percent compared with those of wildtype mice. And the mice showed changes in the expression of genes involved in synaptic plasticity.

Brain slices revealed that the SYNGAP1 mice also had impaired long-term potentiation, the process by which synapses strengthen to facilitate learning and memory. In line with that finding, these mice less frequently went into the arms of a y-shaped maze they had not recently explored than did wildtype rodents.

That behavior indicates the mice might not recall the arm they were in last, which generally reflects deficits in working memory. The mice also displayed hyperactive and repetitive behaviors, typical characteristics in SRID. The results were published in PNAS in September.

I think its an exciting time. There is a lot of increased interest in SYNGAP.

A

The mice showed altered SYNGAP1 functioning that in turn affected synapse functioning, which, would suggest it could increase your risk for developing some sort of mental health disorder, Rumbaugh adds.

This work also reveals that a decrease in SYNGAP1 protein may be a crucial mechanism for the development of SRID. Researchers are already looking for ways to restore the SYNGAP1 protein to treat people with SRID and other neurodevelopmental conditions.

For example, one antisense oligonucleotide a short molecule of DNA or RNA increased the levels of SYNGAP1 in mice in a study published in Neuron in March. Yet another approach to intervention could involve new molecular technology that binds to mRNA and regulates gene expression. The resulting tool brings together the protein-producing machinery for a specific gene, according to a study published in Nature Communications in October.

With this technology, it is possible to elevate SYNGAP1 protein levels in neurons derived from induced pluripotent stem cells that lack one copy of the gene. The approach may open a new avenue for treating conditions such as SRID that are caused by the absence of a functional gene.

[SRID] kids have no direct treatments, says study investigator Bryan Dickinson, professor of chemistry at the University of Chicago in Illinois. There is a critical unmet medical need.

The new mouse strains also offer important therapeutic possibilities. These are actual patient mutations, and that is really cool, says Jill Silverman, professor of psychiatry and behavioral sciences at the University of California, Davis MIND Institute, who was not involved in any of the recent studies.

Its very innovative and important for precision medicine, Silverman says. The sky is the limit.

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SYNGAP1 findings illuminate links between mutations, intellectual disability - The Transmitter: Neuroscience News and Perspectives

How to keep neuroscience’s past racism from being its future – STAT – STAT

De-Shaine Murray is working at the cutting edge of neurotechnology. As a postdoctoral fellow at Yale, he is developing a device to monitor the brain following traumatic brain injury or stroke.

He is also trying to fight the long legacy of racism in neuroscience. During 2020, when it was difficult to conduct research, he said, I got the chance and the ability to read more widely and to just look into the legacy of neuroscience. He found a direct line from racist pseudoscience like phrenology to disparities in neuroscience today, like how the texture of Black peoples hair can sometimes exclude them from clinical trials because electrodes are not designed for them. In 2021, he co-founded Black in Neuro, an organization dedicated to improving Black representation in neuroscience.

On this episode of the First Opinion Podcast, I spoke to him about how the past and present racism in neuroscience could be reflected in the future, especially as neurotechnology like brain implants become more common.

Im not saying that whatever electrode that you made or created is racist. But when you have someone who creates a technology but doesnt think about the wide range of users that are potentially going to use it, then thats where the problem comes in, he told me.

We also discussed the way inequities in neuroscience research are visible in stroke wards, how brain implants might jump from helping disabled people to being used for human enhancement, and more.

Our conversation was inspired by his recent First Opinion essay, Neuroscience has to grapple with a long legacy of racism if it wants to move into the future. The book I mention at the end is Lock In by John Scalzi, a great sci-fi mystery exploring themes of race, socioeconomic status, neurotechnology, and more.

Be sure to sign up for the weekly First Opinion PodcastonApple Podcasts,Spotify,Google Play, or wherever you get your podcasts. And dont forget to sign up for theFirst Opinion newsletterto read each weeks best First Opinion essays.

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How to keep neuroscience's past racism from being its future - STAT - STAT

Social and Affective Neuroscience of Autism (SANA) Lab – Yale School of Medicine

The Social and Affective Neuroscience of Autism (SANA) lab focuses on early social and affective development of children with autism and other neurodevelopmental conditions. We aim to discover biomarkers of social and emotional vulnerabilities and novel treatment targets in infancy and early childhood. Our highly interdisciplinary and collaborative research relies on integration of cutting edge clinical behavioral, neurophysiological, and imaging data in service of improving the lives of children living with complex developmental disorders. The blog will highlight our research, staff, and resources. The first blog features two studies that are actively recruiting infants and young children.

This study of emotional development will help us develop better methods for early diagnosis and intervention for behavioral and emotional challenges. It addresses an understudied yet important area by examining emotional vulnerabilities amongst infants with a family history of autism and evaluating their contribution to later emotional and behavioral difficulties. We are recruiting infants 4 months of age or younger with or without a family history of autism (e.g., siblings, parents, aunts, uncles, or cousins). Participation will include fun and family-friendly follow-up visits through 30 months of age and include assessment of social, adaptive, cognitive, and language development; studies of attention involving watching brief videos; and play-based activities to assess your childs emotional development. https://medicine.yale.edu/lab/chawarska/participate/newborns/

This study focuses on the development of repetitive movements. The study will help us better understand the causes and developmental course of repetitive behavior in children. These typically consist of rhythmic movements that do not appear to serve a specific purpose, and may include flapping, posturing, waving, rotating, or tensing of body parts. Repetitive movements are frequently observed in autism, developmental delays, ADHD, anxiety, and other conditions; they have also been reported in children otherwise developing typically. For some, repetitive movements begin to manifest in infancy; for others, they emerge during the first years and tend to persist throughout childhood and adolescence. We are recruiting children 4 years of age and younger with repetitive motor behavior, either typically developing or with autism or other neurodevelopmental conditions such as ADHD. Participation will include a visit to the lab where your child will have a comprehensive diagnostic evaluation, assessment of repetitive behavior, studies of attention, and collection of saliva samples to learn more about genetic factors involved in repetitive behavior. https://medicine.yale.edu/lab/chawarska/participate/young-children

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Please share this information with families who may be interested.

Submitted by Gitta Selva on December 20, 2023

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Social and Affective Neuroscience of Autism (SANA) Lab - Yale School of Medicine