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Molecular control of macroscopic forces drives formation of the vertebrate hindgut
No full textAuthors Nerurkar, Lee, and Tabin are affiliated with Harvard Medical School, while Mahadevan is affiliated with Harvard University, including the School of Engineering & Applied Science and Arts & Sciences.The embryonic gut tube is a cylindrical structure from which the respiratory and gastrointestinal tracts arise 1. Despite investigations into early emergence of the endoderm as an epithelial sheet 2,3 and later morphogenesis of the definitive digestive and respiratory organs 4–6, the intervening process of gut tube formation has been severely understudied, particularly over the past 45 years 7,8. Here we investigate the molecular control of macroscopic forces underlying early morphogenesis of the gut tube in the chick embryo. The gut tube has been described as forming from two endodermal invaginations – the Anterior Intestinal Portal (AIP) towards the rostral end of the embryo and the Caudal Intestinal Portal (CIP) at the caudal end – that migrate toward one another, internalizing the endoderm until they meet at the yolk stalk (umbilicus in mammals) 1,6. Migration of the AIP to form foregut has been descriptively characterized 9,10, yet the hindgut likely forms by a distinct mechanism that has not been fully elucidated 11. We find that the hindgut forms by collective cell movements through a stationary CIP, rather than via movement of the CIP itself. Moreover, combining in vivo imaging, biophysics, and mathematical modeling with molecular and embryological approaches, we identify a contractile force gradient that drives cell movements in the hindgut-forming endoderm, permitting tissue-scale posterior extension of the forming hindgut tube. The force gradient, in turn, is established in response to a morphogenic gradient of FGF signaling. As a result, we propose that an important positive feedback arises, whereby contracting cells draw passive cells from low to high FGF levels, recruiting them to contract and pull more cells into the elongating hindgut. In addition to providing new insight into the early gut development, these findings illustrate how large-scale tissue level forces can be traced to developmental signals during vertebrate morphogenesis.Accepted Manuscrip
Elizabeth Blackwell: First Female MD and Extraordinary Personality in American Medicine
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Heterozygous mutations cause genetic instability in a yeast model of cancer evolution
No full textGenetic instability, a heritable increase in the mutation rate, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damaging both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivating one copy of a gene whose product is present in limiting amounts (haploinsufficiency5), but determining the relative importance of these two mechanisms is difficult. In E. coli6, applying repeated, strong selection enriches for genetic instability. We used this approach to evolve genetic instability in diploid cells of the budding yeast, Saccharomyces cerevisiae and isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations and engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivate one copy of haploinsufficient genes are more common than those that dominantly alter the function of the mutated gene copy. The mutated genes are enriched for genes functioning in transport, protein quality control, and DNA metabolism, and reveal new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologs or close homologs) of the targets we identified have homologous human genes implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near haploid human cell line: five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologs initiate genetic instability in cancer.Molecular and Cellular BiologyAccepted Manuscrip
Light-induced cortical excitability reveals programmable shape dynamics in starfish oocytes
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Nishimori transition across the error threshold for constant-depth quantum circuits
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Pierre Louis and the Numerical Method: The Development of Evidence-Based Medicine in France and the United States (1820–1860)
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Antis: How Online Fan Spaces Are Repurposing Conservative Religious Rhetoric
No full textOne can learn a lot about a person based on their social media of choice. No one considered ‘young' uses Facebook anymore—but where have they moved? Despite being considered “dead” by many after its infamous adult content ban in December of 2018, the social media website Tumblr, founded in 2007, is still a viable option—it's even (re)branded itself as a friendlier (albeit less user intuitive) alternative to X, formerly Twitter. While Tumblr is not a new website, it is host to all sorts of discourse—not the strictly academic kind, but rather that which is produced by a specific group of people who most would call “chronically online.” This paper explores one aspect of this online discourse, specifically as it relates to antis, who can be seen reiterating conservative/right-wing religious rhetoric in their crusade against darker aspects of fiction.Author's Origina
Critical quantum liquids and the cuprate high temperature superconductors
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Single-cell Genomics of Post-mitotic Human Tissues in Aging and Disease
No full textSomatic mutations occur in human tissues due to errors in DNA replication and DNA damage repair during aging as well as under disease conditions. Previous studies have focused on somatic mutations in clonal cell populations, such as tumors, and found that specific somatic mutations are critical in driving cancer progression. However, the prevalence and impact of somatic mutations in post-mitotic tissues remain largely unknown. Recent advancements in single-cell whole-genome sequencing (scWGS) technologies have enabled us to detect these private mutations. This thesis aims to characterize somatic mutations in single human neurons using scWGS to better understand the role of somatic mutations in neurodegeneration.
Whole-genome duplex consensus sequencing has emerged to provide an enhanced accuracy of mutation calling at the single-molecule level as two DNA strands are sequenced independently to form consensus calls. Duplex sequencing can be applied to both bulk tissues and single cells. Existing tools focus on detecting single-nucleotide variants (SNVs) and often neglect other types of mutations such as small insertions and deletions (Indels). The first aim of this thesis was to develop a computational pipeline for somatic Indel calling in duplex sequencing data to allow more comprehensive somatic mutation characterization. Benchmarking analysis on cancer cell lines demonstrated the accuracy and robustness of the pipeline.
The second and third aims of this thesis focused on the burden and pattern of somatic mutations in neurodegeneration. Chronic traumatic encephalopathy (CTE), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are neurodegenerative diseases with distinct neuropathologies. The work presented in the second aim profiled somatic SNVs and Indels in single neurons from CTE individuals, revealing significantly elevated somatic mutation burdens in CTE compared to neurotypical controls. Comparisons between CTE and AD pointed to potentially common mutagenic processes underlying the two diseases. The third aim turned to ALS and FTD, two closely related neurodegenerative conditions with nuclear TDP-43 depletion as the hallmark, and unveiled a recurrent and widespread pattern of somatic Indels shared by all four neurodegenerative diseases.
This thesis investigates how somatic mutations accumulate in human neurons across multiple major neurodegenerative conditions and highlights the application of the latest sequencing technologies in making biological discoveries. Furthermore, this thesis can serve as the basis for an array of future studies. The new pipeline can be applied to other tissues, and the recurrent somatic Indel pattern may provide valuable insight into identifying potential therapeutic targets for a broad range of neurodegenerative diseases.Biomedical Informatic
Altered Social Information Processing and Behavioral Responsivity as Mechanisms Linking Childhood Experiences of Violence with Psychopathology
No full textIn the United States, over half of youth experience or witness interpersonal violence. Extensive research links these experiences with heightened risk for developing mental health problems throughout life. Despite advances in our understanding of how early violence exposure impacts mental health, there remains a need to refine translational mechanisms to guide intervention efforts. This dissertation leverages theory and methods from clinical, developmental, and social psychology to characterize the interplay of early-life violence exposure with the development of information processing patterns that hold relevance for mental health and patterns of aggressive behavior that may underlie or maintain “cycles of violence.” Paper 1 utilizes a three-timepoint longitudinal design, developmental sample, and experimental manipulation to test whether alterations in implicit bias for novel groups is a mechanism linking childhood violence exposure with prospective risk for internalizing symptoms. Paper 2 attempts to replicate and extend findings from Paper 1 in a larger sample of young adults to test whether alterations in implicit social cognition following violence exposure persist into adulthood, and to
examine whether early violence exposure similarly impacts affect biases relevant to social cognition and mental health. Paper 3 aims to characterize behavioral risk factors for becoming violence-involved that are informed by similar social and affective information processing biases using an ecologically-valid aggression paradigm in a high-risk adolescent sample. Together, findings from this dissertation suggest that subconscious intergroup biases, such as implicit bias for novel groups, may be an important mechanism linking early violence exposure with risk for mental health, and implicate the development of aggressive response styles as a risk factor for perpetrating violence. Future directions are discussed throughout and in the general discussion.Psycholog