Effects of Child Care Vouchers on Price, Quantity, and Provider Turnover in Private Care Markets

Harnessing changes in funding for a voucher program that subsidizes consumers’ use of child care services at private providers, this study quantifies effects on local markets’ service capacity and prices. We also estimate how increased funding effects provider entry rate, exit rate, and highly rated provider market share. The evidence shows that an additional $100 in private voucher funding per local young child would 1) raise the number of private-provider slots by 0.026per local young child, 2) raise average prices by$0.56 per week, mainly driven by a price increase among incumbent providers, and 3) induce new provider entry to the market by 0.4 percentage points. The estimates imply a highly elastic supply elasticity of 10.7. Thus an increase in public funding and subsequent increase in demand is expected to result in expansion of available slots accompanied by a limited increase in price

High Force Unimanual Handgrip Contractions Increase Ipsilateral Sensorimotor Activation and Functional Connectivity

Imaging and brain stimulation studies seem to correct the classical understanding of how brain networks, rather than contralateral focal areas, control the generation of unimanual voluntary force. However, the scaling and hemispheric-specificity of network activation remain less understood. Using fMRI, we examined the effects of parametrically increasing right-handgrip force on activation and functional connectivity among the sensorimotor network bilaterally with 25%, 50%, and 75% maximal voluntary contractions (MVC). High force (75% MVC) unimanual handgrip contractions resulted in greater ipsilateral motor activation and functional connectivity with the contralateral hemisphere compared to a low force 25% MVC condition. The ipsilateral motor cortex activation and network strength correlated with relative handgrip force (% MVC). Increases in unimanual handgrip force resulted in greater ipsilateral sensorimotor activation and greater functional connectivity between hemispheres within the sensorimotor network. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved

Predicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network

Cryptic pockets expand the scope of drug discovery by enabling targeting of proteins currently considered undruggable because they lack pockets in their ground state structures. However, identifying cryptic pockets is labor-intensive and slow. The ability to accurately and rapidly predict if and where cryptic pockets are likely to form from a structure would greatly accelerate the search for druggable pockets. Here, we present PocketMiner, a graph neural network trained to predict where pockets are likely to open in molecular dynamics simulations. Applying PocketMiner to single structures from a newly curated dataset of 39 experimentally confirmed cryptic pockets demonstrates that it accurately identifies cryptic pockets (ROC-AUC: 0.87) \u3e1,000-fold faster than existing methods. We apply PocketMiner across the human proteome and show that predicted pockets open in simulations, suggesting that over half of proteins thought to lack pockets based on available structures likely contain cryptic pockets, vastly expanding the potentially druggable proteome

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder

Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD

Drug-induced chromatin accessibility changes associate with sensitivity to liver tumor promotion

Liver cancer susceptibility varies amongst humans and between experimental animal models due to multiple genetic and epigenetic factors. The molecular characterization of such susceptibilities has the potential to enhance cancer risk assessment of xenobiotic exposures and disease prevention strategies. Here, using DNase I hypersensitivity mapping coupled with transcriptomic profiling, we investigate perturbations in cis-acting gene regulatory elements associated with the early stages of phenobarbital (PB)- mediated liver tumor promotion in susceptible versus resistant mouse strains (B6C3F1 versus C57BL/6J). Integrated computational analyses of strain-selective changes in liver chromatin accessibility underlying PB-response reveal differential epigenetic regulation of molecular pathways associated with PB-mediated tumor promotion, including Wnt/-catenin signalling. Complementary transcription factor motif analyses reveal mouse strain-selective gene regulatory networks and a novel role for Stat, Smad and Fox transcription factors in the early stages of PB-mediated tumor promotion. Mapping perturbations in cis-acting gene regulatory elements provides novel insights into the molecular basis for susceptibility to xenobiotic-induced rodent liver tumor promotion and has the potential to enhance mechanism-based cancer risk assessments of xenobiotic exposures

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Applications of Demand Estimation to the Child Care Market

University of Minnesota Ph.D. dissertation. July 2020. Major: Economics. Advisor: Thomas Holmes. 1 computer file (PDF); vi, 91 pages.This dissertation presents three studies that apply discrete choice demand estimation techniques to policy-focused questions regarding the Minnesota child care market. The first study analyzes provider quality ratings provided through Minnesota's Parent Aware program. The demand system is estimated on provider level data using the method of Berry et al. (1995). Welfare estimates are computed for the value of the ratings to consumers in different locations. Variation in local value of the ratings is driven by density of providers. The value of the ratings is high in most areas with a high concentration of low-income consumers. The second study uses administrative micro-data on subsidized consumers from Minnesota's Child Care Assistance Program, focusing on the role of distance in child care choice. A nested logit model is estimated that simultaneously models the choice of individual provider and the choice between center-based and family providers. The results provide new evidence on the importance of proximity and the geographic scope of child care markets. We present two applications. First, we present a construct for measuring the geographic scope for a policy intervention and analyze how it varies in urban, suburban, and rural areas. Second, we show that differences in what types of providers are available nearby explains most of the difference between White, Black, and Hispanic households in the use of center-based care. The third study uses a simplified version of the same nested logit choice model as a lens to analyze trends in use of family providers. We simulate counterfactuals that measure the importance of different factors, showing that decline in the availability of family providers and changes in the location and demographic composition of the CCAP population are the most important factors explaining the decline in the rate of use of family providers by CCAP consumers