The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Strong Female Characters ? An Analysis of Six Female Fantasy Characters from Novel to Film

This project is twofold. The first section analyzes six female fantasy characters in their literary and filmic incarnations—Dorothy Gale (The Wizard of Oz), Susan Pevensie (The Chronicles of Narnia: Prince Caspian), Arwen Evenstar (The Lord of the Rings), Princess Buttercup (The Princess Bride), Hermione Granger (Harry Potter and the Sorcerer’s Stone), and Annabeth Chase (Percy Jackson and the Olympians: The Lightning Thief)—noting adaptational changes made to each and placing the twelve incarnations in conversation with each other. This conversation centers around the concept of the “strong female character,” and this study attempts to define the qualifications of a true “strong female character,” distinguished from a “hyper-strong” stereotype, and show how each of these twelve incarnations meets or fails to meet those qualifications. The second section is an excerpt from my novel-in-progress Ogelzetrap, followed by analysis of my female characters and how I’ve crafted them to avoid pitfalls of harmful literary and cinematic norms

Computational Methods for Accelerated Discovery and Characterization of Genes in Emerging Model Organisms

Cilia are evolutionarily conserved, complex, microtubule-based structures that protrude from many eukaryotic cells. In humans, cilia can be found on almost all cell types. The effect of abnormal or absent cilia has been established as the common underlying cause of a recently emerging class of genetic diseases collectively referred to as ciliopathies. The function and structure of cilia are conserved across all organisms with cilia. One of the most influential model systems used to study ciliopathies has been the ciliated green alga Chlamydomonas reinhardtii, an organism for which there is a sequenced genome with relatively few experimentally validated whole-gene annotations but in which the ciliogenesis process can be reliably induced. Experimental methods have been successful in identifying a handful of highly specific cilia disease genes in the alga, but high-throughput, automated computational analyses harbor the greatest potential to reveal a more comprehensive ciliopathy disease gene list. However, ii in order for a genome to be informative for downstream computational analyses, it must first be accurately annotated. This dissertation focuses on accelerating the accurate annotation of the Chlamydomonas genome using whole-genome and whole-transcriptome methodologies to identify human ciliopathy genes. Towards this end, we first develop a genefinder training method for Chlamydomonas that does not require whole gene annotations and demonstrate that this traning method results in a more accurate genefinder than any other genefinder for this alga. Next, we develop a new automated protein characterization method that facilitates the transfer of information across different protein families by extending simple homology categorization to identify new cilia gene candidates. Finally we perform and analyze high-throughput whole-transcriptome sequencing of Chlamydomonas at various timepoints during ciliogenesis to identify ~300 novel human ciliopathy gene candidates. Together these three methodologies complement each other and the existing literature to better elucidate a more complete and informative cilia gene catalog

The Glass Ceiling and Persons With Disabilities

Glass Ceiling ReportGlassCeilingBackground2PersonsWithDisabilities.pdf: 8336 downloads, before Oct. 1, 2020

Accessing Academe, Disabling the Curriculum: Institutional Locations of Dis/ability in Public Higher Education

The field of Disability Studies has long committed itself to the project of making American colleges and universities more accessible places for disabled faculty, staff, and students. Indeed, many of the field of early ideological roots of the discipline of Disability Studies (DS) emerged from campus-based activist movements. This influence has impacted the ways DS scholars continue to frame their intellectual labor as a progressive public good. In recent years, composition/rhetoric scholars have begun applying DS approaches to questions of pedagogical and professional access as well. These critiques have drawn attention the ways teaching practice, administrative policy, and other aspects of academic life are undergirded by many of the same ableist values that pervade other professional environments. This dissertation investigates the history of disability-related institutional work in the City University of New York across three distinct periods: I use archival analysis to discuss New York City’s unique municipal college system’s early 20th century programs, which defined disability access in terms of a medical rehabilitation model; second, I use oral history to document important institutional changes that came to CUNY (which was officially organized only in 1961) during the 1970s, when students began organizing disability activist coalitions and CUNY began institutionalizing system-wide disability services; finally, I draw from unofficial archives and further oral histories to examine the impacts of the rise in learning and other invisible disabilities in CUNY in the 1980s and 90s. This history demonstrates both the complex problem of designing equitable programs for disability access, and the generative possibilities of incorporating disability into the mainstream mission of higher education

Understanding User Cognition: From Spatial Ability to Code Writing and Review

Understanding how developers carry out different computer science activities with objective measures can help to improve productivity and guide the use and development of supporting tools in software engineering. In this thesis, we present three research components using three different objective measures including neuroimaging (functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS)) and eye tracking. We evaluate on over 140 human subjects to explore multiple computing activities, including data structure manipulations, code writing and code review. This thesis presents a systematic framework and shows that it is possible to conduct studies that acquire objective data in a natural setting to provide an understanding of users' underlying cognitive processes in software engineering tasks. We also provide basic principles and guidelines to adapt multiple psycho-physiological measures to software engineering.PHDComputer Science & EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169678/1/yhhy_1.pd