Alliance One Tobacco (Malawi)
Academic Research Repository at the Institute of Developing EconomiesNot a member yet
52305 research outputs found
Sort by
Mild pH-decoupling aqueous flow battery with practical pH recovery
No full textEngineering and Applied SciencesVersion of Recor
Polymerization of ZBTB transcription factors
No full textThe regulation of gene expression at the level of transcription is essential and underlies critical processes such as maintaining cell identity and orchestrating development. Transcription factors (TFs) play critical roles in this process and therefore themselves are subject to complex regulatory processes. Many TF families form complex higher-order structures, ranging from simple dimers to large multi-protein complexes, to regulate gene expression with greater efficiency and precision.
The broad-complex, tramtrack and bric-à-brac (BTB) family of TFs serve as important regulators of hematopoietic development. Their characteristic BTB domain mediates protein-protein interactions, such recruitment of co-repressors, as well as homomeric assemblies, including dimers, tetramers, pentamers, and hexamers. BCL6, a master TF of germinal center B cells, forms a homodimer through its BTB domain to mediate transcriptional repression by recruiting its co-repressor proteins. Recently, we reported that BCL6 forms polymers in the presence of a small-molecule molecular glue that stabilizes a complementary interface between homodimers of BCL6’s BTB domain. The BTB domains of other proteins, including a large class of TFs, have similar architectures and symmetries, but their propensity to self-assemble into higher-order structures has not been established.
In my thesis work, we survey 189 human BTB proteins with a cellular fluorescent reporter assay and uncover a novel phenomenon in which 18 zinc finger and broad-complex, tramtrack and bric-à-brac (ZBTB) TFs undergo polymerization under normal physiologic conditions. Furthermore, we present structural and biochemical data demonstrating that three ZBTB TFs – ZBTB3, ZBTB5, and ZBTB9 – polymerize into filaments in vitro. Through ChIP-Seq and RNA-Seq analyses, we identify that wild-type ZBTB polymers bind DNA better than their non-polymerizing mutant counterparts. Importantly, these polymers selectively bind homotypic clusters of repeated TF binding sites, thereby enhancing the transcriptional repressive function of these transcription factors.
This systematic study of ZBTB TF polymerization provides a novel framework to better understand regulation of this important class of TFs. Currently, instances of human TFs polymerizing in the absence of DNA are scarce. Our finding of ZBTB TF polymerization implies that this phenomenon could be more widespread, highlighting a potentially common and functionally significant aspect of transcription factor behavior.Medical SciencesMedical Science
Dignity, Job Quality, and Mobility in the U.S. Service Sector
No full textThe nature of low-wage work in the United States has fundamentally changed over the past fifty years. These jobs have become increasingly precarious, manifest in stagnant wages, unstable and unpredictable schedules, limited fringe benefits, and lower job security. This is particularly true in the service sector, which now accounts for almost one in five jobs in the U.S. While a robust body of work has examined the causes and consequences of this rising precarity, this dissertation addresses two overarching gaps in the extant literature on precarious work. First, research on precarious work has been mostly siloed from research on dignity at work, so our understanding of the drivers of workplace dignity in the service sector, and its associated consequences, is limited. Second, while scholarship has extensively studied the degree of upward wage mobility from low-wage jobs, less work has considered improvements in job quality more multidimensionally or the labor market contexts and mechanisms that foster such improvement.
To address these questions, I draw on novel cross-sectional and longitudinal data from The Shift Project, a web-based survey of service sector workers in the United States that uses advertisements on Facebook and Instagram to target and recruit workers into the sample. I bring together the literatures on dignity, precarious work, and turnover to explore how job conditions that are characteristic of low-wage work in the service sector are associated with workplace dignity, and, in turn, what the consequences of workplace dignity are for employee turnover. Furthermore, I use the case of the “Great Resignation” to study how local labor market conditions shape workers’ probability of transitioning into “good” jobs, defined multidimensionally, as well as how this varies by employment pathway.
Chapter 2 explores how service sector workers' unstable and unpredictable schedules are associated with their experiences of dignity in the workplace, manifested in perceptions of respect and fair treatment from their supervisors. I find that schedule instability is strongly and negatively associated with worker dignity, including five just-in-time scheduling practices (experiencing a canceled shift, changed timing to shift, working an on-call shift, working a “clopening” shift (i.e., when a worker both closes one night and opens the following morning after only a few hours of rest) and an index that captures cumulative exposure to schedule instability. Furthermore, I show that the significant relationship between dignity at work and schedule instability is more negative for women than men: while women in low-instability environments report higher dignity at work than men, this inverts at higher levels of instability, where women report lower dignity than men. I posit that the more negative relationship I identify between instability and dignity for women is, in part, driven by work-family conflict.
Chapter 3 then examines the consequences of lacking dignity at work, specifically on voluntary employee turnover, a key employee work behavior with notable implications for organizational performance. I find that while experiences of respect and bullying from customers, coworkers, and supervisors are each significantly associated with workers' stated intentions to find a new job, only respect and bullying from supervisors is significantly associated with actual turnover behavior, a gap I argue can be partially explained by the differences in the power and permanence of these social relationships. I also show that supportive coworker relationships actually increase workers' propensity to leave their jobs in low-dignity environments, evidence that social support can empower workers to leave toxic working environments.
Chapter 4 explores how workers' job quality changes in tight labor markets, and how this varies by employment pathway (i.e., job staying vs. leaving). This chapter is co-authored with colleagues from the Shift Project (Dylan Nguyen, Daniel Schneider, and Kristen Harknett), and I am lead author. We develop a multidimensional conceptualization of a "good job" that includes a living wage of $15/hour, low schedule instability, and a suite of critical benefits (health insurance, retirement, and paid sick leave). Drawing on longitudinal data that span the period before and during the “Great Resignation,” we find that transitions into such jobs are relatively low, but this varies by local labor market conditions: workers in tight labor markets (e.g., during the Great Resignation) are more likely to transition into good jobs, particularly those who transition out of the service sector
Overcoming the streetlight effect: Shining light on the foundations of learning and development in early childhood.
No full textDevelopmental theory has long emphasized a range of skills that young children need for healthy development across the life course. Nevertheless, most evaluations of early childhood programs and policies have focused on measuring a somewhat limited set of competencies. In this article, we explore this “streetlight effect” in early childhood intervention research and propose an initial set of skills that we argue are the foundations of learning and development (FOLD skills) and accordingly should be prioritized alongside traditionally measured outcomes as targets of intervention during the preschool period (i.e., between ages 3-5 years). These FOLD skills include both well-studied and emerging constructs such as curiosity, creativity, self-regulation and executive function, critical thinking, perspective taking, and internal representations of self. To better understand FOLD skills’ potential as more practical, effective, and inclusive targets of early childhood programs and policies, we review research regarding each skill’s malleability, measurability, predictive validity, and universality. We end with a set of future directions for the field, including the need to: (1) formulate a more inclusive taxonomy of FOLD skills that incorporates currently omitted competencies relevant to marginalized populations; (2) measure these skills in scalable and actionable ways; and (3) enhance or modify intervention strategies to optimize the development of these FOLD skills in the preschool period.Accepted Manuscrip
Surface display of proteins on bone marrow-derived dendritic cells induces humoral immune responses and anaphylaxis
No full textWhile the presentation of peptides on major histocompatibility (MHC) molecules by dendritic cells (DCs) for T cell activation has been extensively documented, it has been unclear if DCs express surface receptors that can selectively exhibit unprocessed proteins for extended periods of time for recognition by B cells. We show here that murine bone marrow-derived DCs (BMDCs) incubated with serum proteins displayed these proteins on their surface and, when injected into recipient mice, induced the production of protein-specific antibodies. Subsequent challenge of BMDC-vaccinated recipient mice with these same serum proteins triggered severe anaphylaxis. Antigen-specific IgE was not necessary to mediate severe anaphylaxis in these challenged mice, while mast cell activation, though also dispensable, was an important contributor to the overall anaphylactic response. In our model, proteins must be displayed on the surface of BMDCs to generate a robust antibody response and this process simultaneously required MHC class II presentation. Furthermore, germinal centers were necessary to generate this humoral response: mice lacking T follicular helper cells were not able to generate robust, presumably high-affinity, IgG and IgE responses to the proteins displayed by the transferred BMDCs. Intriguingly, while murine BMDCs could display proteins from both bovine serum and human serum, there was selectivity in the specific proteins they displayed. This selectivity resulted in differential humoral responses in recipient mice. Specifically, transferred murine BMDCs displayed and generated a humoral response to human serum albumin; in contrast, these BMDCs only minimally displayed bovine serum albumin found within fetal bovine serum and could not generate a robust humoral response against it. Previous work has demonstrated that in addition to processing and presenting peptides, DCs may be involved in presenting proteins to B cells. We show here that specific protein display (as distinguished from peptide antigen presentation) may be a function of DCs that contributes in some contexts to humoral immunity.Medical SciencesMedical Science
A mechanosensory neural pathway mediating wet dog shakes
No full textDogs and other mammals perform stereotypical rapid oscillations of their head and upper trunk to remove water and other irritants contacting their back hairy skin, a behavior known as wet dog shakes. The somatosensory mechanisms underlying this stereotypical behavior are poorly understood. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to the dorsal neck hairy skin of mice. A survey of mechanosensory neuron types that underlie stimulus-evoked wet dog shakes revealed that unmyelinated low-threshold mechanoreceptors (C-LTMRs), which form lanceolate endings associated with vellus body hair follicles and had been implicated in affective, pleasurable touch, mediate this behavioral response to mechanical stimuli. C-LTMRs were strongly activated by oil droplets applied to hairy skin and, unlike several other LTMR types, their optogenetic activation evoked wet dog shakes. Moreover, ablation of C-LTMRs attenuated oil droplet evoked wet dog shakes. Centrally, we found that C-LTMRs are synaptically coupled to spinoparabrachial neurons, and optogenetic inhibition of spinoparabrachial neuron synaptic transmission and excitatory neurons of the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR-spinoparabrachial pathway mediates wet dog shakes to remove water and possibly other mechanical irritants contacting back hairy skin.Medical SciencesMedical Science
Correlations in Random Graphs and Mean-Field Spin Glasses
No full textRandom graph models, e.g. the Erdös-Rényi model, are central objects in computer science. Ran-
dom graph theory sheds light on the typical behavior of graphs such as connectivity, degree distri-
bution, and expansion. On the other hand, by considering random graphs as networks that describe
social, biological, and technical structures [DT19], combinatorial problems on random graphs have
applications in machine learning, network de-anonymization, and computational biology.
To obtain a more realistic model for some real-world scenarios, sometimes it is beneficial to consider
correlated samples from the random graph model, where correlation can be thought of as a soft
representation of the underlying structure. For example, contacts of users in two social networks are
expected to be related. In this thesis, we consider the graph matching problem on correlated random
graphs. In the first part of the thesis, we give an efficient algorithm that recovers a matching between
two correlated random graphs without using any ”seed”. We then provide an application of random
graph matching to a problem in computational biology. In particular, we propose an algorithm
that recovers cell structures, where graphs are nearest neighbor graphs based on gene expression
distance from single-cell RNA-seq dataset, without using prior information. For both problems, the
algorithm found ways to capture structure from underlying correlation instead of requiring prior
information on the underlying structure.
Connections between spin glasses and random graphs have been investigated in recent years [MM09,
Sen17, MM11]. In the second part of the thesis, we study a generalization of the SK model, the
mean-field Ghatak-Sherrington Model. We establish the limiting distribution of the (self) overlap
array and the free energy at sufficiently high temperature, by investigating the structure that arises
from the correlation between coordinates of the spin configuration
The T1D Fund: A Disruptive Philanthropic Model to Accelerate Cures
No full textIn 2015, despite decades of promising research and a large and passionate patient advocacy community, almost no companies were working on curing type one diabetes (T1D). Since then, there has been over USD800 million of venture investment in about 40 companies working on T1D cures, with several billion dollars more in public market investment and money invested to buy several of these companies. The first therapy that intervenes and delays progression of the disease was approved in 2022.
This is the story of the transformation of the fight to cure a prevalent disease using an innovative philanthropic impact investing fund, born under the aegis of a public charity willing to take a risk and powered by over USD100 million of donations from just over 100 affected families. The T1D Fund, which launched in 2016, catalyzed a market to cure T1D and drove these dramatic developments. It may have cracked the code on perhaps one of the most vexing challenges facing disease philanthropies and research scientists across the country and around the world: what is the best way to accelerate the translation of promising research into potential drugs that can run the complicated and expensive gauntlet of our pharmaceutical sector and get delivered to patients?
The T1D Fund model tailored its strategy to capitalize on the complementary strengths of different parts of the life sciences ecosystem. Disease philanthropies build unparalleled knowledge and network through the best research. But the private sector alone, both because overwhelming financial advantages and differentiated expertise, has the power to select and develop the drug candidates that present not only great science but also solid and attractive business potential. Our Fund developed a novel approach that navigated and joined these capabilities. It is working, and it offers a model and some lessons for other disease philanthropies seeking to drive the development of cures.Author's Origina
Single-neuronal elements of speech production in humans
No full textHumans are capable of generating extraordinarily diverse articulatory movement combinations in order to produce meaningful speech. This ability to orchestrate specific phonetic sequences, their syllabification and inflection over sub-second timescales allows us to produce thousands of word-sounds and is a core component of language 1,2. The basic cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh density Neuropixels recordings in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events prior to utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also reliably predicted the phonetic, syllabic and morphological components of upcoming words and displayed a temporally ordered dynamic. Taken collectively, we show how these cells were spatially organized and how their activity patterns transitioned from articulation planning to production in real-time. We also demonstrate how they tracked the composition of phonemes during perception, and how they distinguished processes specifically related to speaking from listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and a cellular process that can support the production of natural speech.Accepted Manuscrip
Polygenic architecture of human body size and proportion
No full textOver the last 15 years, genome-wide association studies (GWAS) have discovered thousands of genetic associations with human phenotypes. However, as most of these associations lie in non-coding regions and are typically spread over a group of highly correlated variants, it remains difficult to draw clear connections from the variant through relevant biological mechanisms to the associated phenotype. The field of genetics has endeavored to address this deficiency in many ways. I have built upon prior findings using various approaches, integrating genetic data from multiple phenotypes and ancestries, to bridge the gap between association and genetic architecture.
My work focuses on phenotypes related to skeletal growth and proportion. I first explored the genetic basis of multiple growth-related proteins. Here, I identified two protein quantitative trait loci (pQTL) associated with serum levels, measured in a childhood Cincinnati cohort, for IGFBP-3, IGF-2, and IGFBP-5. To better understand their effects, we explored each association’s overlap with adult height as well as related phenotypes including sitting height ratio (SHR), a measure of skeletal proportion, and birth weight (BW). Mendelian Randomization (MR) supports a causal relationship between protein levels and SHR (for an association near IGFBP3) and BW (for an association near IGFBP5) but not for height. This result suggests that the mechanism by which these proteins affect height must be through some process, perhaps local to the growth plate, not reflected in measured serum levels of these proteins.
I then investigated the genetic basis of SHR, using genetic data from two ancestries to perform the largest GWAS of SHR to date. After identifying 565 independent associations (an increase from 6 in the prior publication), I observed substantial overlap between phenotypes at the level of both the associated loci and implicated genes and pathways. Using fine-mapping, I classified height associations by their effect on body proportion, and showed that those fine-mapped credible sets affecting both height and body proportion are enriched for critical genes for growth. Additionally, these fine-mapping results
enabled me to identify instances where effects on height and body proportion differed across different ancestries.
Lastly, I used various approaches to understand the genetic structure underlying height and other anthropometric traits. I first quantified the extent to which biological pathways implicated by gene set enrichment analysis (GSEA) were “saturated” across increasingly large height GWAS. I then identified genes and gene-sets enriched among height GWAS results, and performed similar analyses in collaboration with GIANT working groups focused on body mass index and waist-hip ratio, and developed comparative GSEA, an approach to identify enriched gene sets that differ between input GWAS. In addition, I quantified levels of population stratification present in height GWAS samples, and re-examined evidence of natural selection acting on loci identified in height GWAS.
Together, the findings and methods described in this dissertation expand our understanding of the biology and genetic architecture underlying measures of human body size and proportion, and contribute novel methodological approaches to understanding correlated phenotypes