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James Edward Deeds, Jr.: A Plea for the Appreciation of Normalcy in Psychiatric Practice
No full textAuthor's Origina
Critical quantum liquids, and the cuprate high temperature superconductors
No full textPhysicsAuthor's Origina
SmartEM: machine-learning guided electron microscopy
No full textConnectomics provides nanometer-resolution, synapse-level maps of neural circuits to understand brain activity and behavior. However, few researchers have access to the high-throughput electron microscopes necessary to generate enough data for whole brain or even whole circuit reconstruction. To date, machine-learning methods have been used after the collection of images by electron microscopy (EM) to accelerate and improve neuronal segmentation, synapse reconstruction and other data analysis. With the computational improvements in processing EM images, acquiring EM images has now become the rate-limiting step in automated connectomics. Here, in order to speed up EM imaging, we integrate machine-learning into real-time image acquisition in a single-beam scanning electron microscope. This SmartEM approach allows an electron microscope to perform intelligent, data-aware imaging of specimens. SmartEM saves time by allocating the proper imaging time for each region of interest – first scanning all pixels rapidly, then rescanning more slowly only the small subareas where a higher quality signal is required. We demonstrate that SmartEM achieves up to a 7-fold acceleration of image acquisition time for connectomic samples using a commercial single-beam SEM in samples from nematodes, mice and human brain. We apply this fast imaging method to reconstruct a portion of mouse cerebral cortex with an accuracy comparable to traditional electron microscopy.PhysicsCenter for Brain ScienceMolecular and Cellular BiologyAuthor's Origina
Convergent and Sex-Differential Genetic Underpinnings of Autism
No full textAutism is a highly heritable neurodevelopmental disorder characterized by restricted or repetitive behaviors and interests as well as challenges with social communication. Epidemiologically, autism is both common – one out of every thirty children in the United States is diagnosed with autism – and strikingly male biased, with three to four males diagnosed with autism for every one female. Twenty years of large-scale sequencing studies of autistic individuals have implicated many genetic variants across many different genetic variant classes in autism, demonstrating its substantial locus heterogeneity and complex genetic architecture. These sequencing studies have also consistently found that autistic females tend to carry a higher genetic load of autosomal autism-associated variation compared to autistic males. That females require more autosomal genetic risk to manifest autism than males suggests that females are somehow intrinsically genetically “protected” from autism, and this phenomenon has thus come to be known as the “female protective effect” (FPE). However, the genetic basis for the FPE remains unknown.
In this dissertation, I address two major questions in autism genetics. First, how do the many diverse genes and genomic loci implicated in autism molecularly converge on this shared phenotype? Second, what mechanisms underlie the reduced genetic susceptibility of females to autism, as evidenced by the FPE? In Chapter 1, I discuss the genetic architecture of autism across three major axes (scale of variation, mode of inheritance, and allele frequency). I then
summarize the evidence supporting the “convergence in autism” hypothesis, which proposes that the significant locus heterogeneity observed in autism can be explained by the convergent disruption of a core set of autism-associated genes and pathways by a wide array of distinct risk loci. Next, I discuss our current understanding of the origins of the male bias and FPE in autism. I emphasize that the male bias in autism cannot be fully explained by underdiagnosis of autistic females or X-linked causes of autism. Rather, the FPE suggests a generally decreased susceptibility of females to autosomal genetic risk for autism—a pattern I show extends to at least sixteen other male-biased congenital, developmental, or pediatric disorders. This suggests a more generalized FPE beyond autism. Finally, motivated by recent insights regarding the “inactive” X (Xi) and Y chromosomes – and particularly the recent realization that Xi and Y act in trans to modulate thousands of autosomal genes across the genome – I propose that a generalized FPE arises from genetic divergence between Xi and Y: the largest, oldest, and most common variation in the human genome.
In Chapter 2, I demonstrate that genetic knockdown of autism risk genes in human neural progenitor cells and cortical organoids leads to convergent transcriptional changes due to shared disruption of a small set of key upstream regulators that coordinate tightly connected gene regulatory networks of autism genes. I further investigate convergence in autism through the creation and analysis of Consensus-ASD, a comprehensive and public-facing database integrating autism-associated variants across seven different genetic variant classes. Finally, I examine the role of X-linked genes, particularly those that are expressed from Xi, in driving both the male bias and FPE within autism.
In Chapter 3, I analyze sequencing data from >400,000 healthy adults in two independent population cohorts to demonstrate that females in the general population harbor a significantly higher burden of deleterious autosomal variation, including both deleterious autosomal deletions and single-nucleotide variants, compared to males. Moreover, I demonstrate that this deleterious autosomal variation is concentrated in highly constrained and dosage- sensitive genes, suggesting that females may be more resilient to disruptions in autosomal gene dosage compared to males. This observation provides important context to the FPE in autism and further suggests a generalized FPE beyond autism, as hypothesized in Chapter 1.
Finally, in the Appendix, I include three additional first-author works from my dissertation research that highlight the role of genetic variation in shaping phenotypes beyond autism, including Alzheimer’s disease, focal cortical dysplasia, and cardiac metabolism. Thus, while the main body of my thesis focuses on the genetics of autism, these additional works from my dissertation illustrate the broader application of genetic and genomic approaches to understanding complex human traits.
In summary, my dissertation provides novel insights into how genetic variation contributes to both shared molecular features of autism and sex-specific patterns of genetic vulnerability.Biomedical Informatic
Adorning The Spirit: Clothing as sacred technology for the Boston Sisters of Perpetual Indulgence
No full textThis paper explores the intersection of queer embodiment, ritualized dress, and sacred space-making through in-depth qualitative research and a cross-theological study of the Boston Sisters of Perpetual Indulgence. This qualitative research paper also includes the beginnings of ethnographic work in this community of Sisters. What was concluded during this time, is that the depth of the community and its individuals deserve much longer and more integrated periods of ethnographic engagement for this single methodology to be the main source of data in a formal study. Therefore, drawing from the fields of anthropology, queer theology, ritual studies, psychology, and mystical philosophy, this research proposes the framework of clothing as sacred technology; a consciously deployed tool for spiritual healing, identity affirmation, and community space-holding.
Throughout religious history, garments have functioned as symbols of spiritual authority, ritual initiation, and divine embodiment. Yet for many queer individuals, access to these sacred roles has historically been denied or rendered conditional by religious institutions rooted in binary gender constructs and exclusionary doctrines. This paper argues that queer communities, exemplified by the Boston Sisters of Perpetual Indulgence, have not abandoned the sacred, but instead created new forms of spiritual practice outside of institutional religion. Through their embodied ministry of radical visibility, performance, and compassionate service, the Sisters seem to engage in a living theology that offers healing for themselves and sanctuary for others who have experienced spiritual and communal exile.
Anchored in Carl Jung’s theories of individuation, Victor Turner’s concept of liminality, James Hillman’s depth psychology, and the mystical understandings of sacred androgyny present across multiple traditions, this paper repositions queer dress as both a site of personal integration and an instrument of communal healing. This is done by addressing and re-addressing these cross-disciplinary viewpoints within the Sisterhood’s unique function as a sacred secular spiritual community. Rather than viewing drag, gender nonconformity, and queer aesthetics as merely performative or political, this research examines these expressions as spiritual acts that align with ancient sacred technologies and anthropological views of transformation.Extension Studie