Assessing the Impact of Non-Pharmaceutical Interventions on Consumer Mobility Patterns and COVID-19 Transmission in the US.

The initial outbreak of COVID-19 during late December 2019 and the subsequent global pandemic markedly changed consumer mobility patterns worldwide, largely in response to government-ordered non-pharmaceutical interventions (NPIs). In this study, we investigate these changes as they relate to the initial spread of COVID-19 within two states-Massachusetts and Michigan. Specifically, we use linear and generalized linear mixed-effects models to quantify the relationship between four NPIs and individuals' point-of-sale (POS) credit card transactions, as well as the relationship between subsequent changes in POS transactions and county-level COVID-19 case growth rates. Our analysis reveals a significant negative association between NPIs and daily POS transactions, particularly a dose-response relationship, in which stringent workplace closures, stay-at-home requirements, and gathering restrictions were all associated with decreased POS transactions. We also uncover a significant positive association between 12-day lagged changes in POS transactions compared to pre-pandemic baselines and county-level COVID-19 case growth rates. Overall, our study supports previous findings that early NPIs reduced human mobility and COVID-19 transmission in the US, providing policymakers with quantitative evidence concerning the effectiveness of NPIs.

Genome Architecture Mediates Transcriptional Control of Human Myogenic Reprogramming.

Genome architecture has emerged as a critical element of transcriptional regulation, although its role in the control of cell identity is not well understood. Here we use transcription factor (TF)-mediated reprogramming to examine the interplay between genome architecture and transcriptional programs that transition cells into the myogenic identity. We recently developed new methods for evaluating the topological features of genome architecture based on network centrality. Through integrated analysis of these features of genome architecture and transcriptome dynamics during myogenic reprogramming of human fibroblasts we find that significant architectural reorganization precedes activation of a myogenic transcriptional program. This interplay sets the stage for a critical transition observed at several genomic scales reflecting definitive adoption of the myogenic phenotype. Subsequently, TFs within the myogenic transcriptional program participate in entrainment of biological rhythms. These findings reveal a role for topological features of genome architecture in the initiation of transcriptional programs during TF-mediated human cellular reprogramming.

4D nucleome Analysis Toolbox: analysis of Hi-C data with abnormal karyotype and time series capabilities.

Motivation: The availability of powerful analysis tools will further understanding of genome organization and its relationship to phenotype in dynamical settings. Results: The 4D Nucleome Analysis Toolbox (NAT) is a user-friendly and powerful MATLAB toolbox for time series analysis of genome-wide chromosome conformation capture (Hi-C) data and gene expression (RNA-seq). NAT can load and normalize data, define topologically associating domains, analyse translocations, produce visualization, and study time course data. We provide examples that include time series data sets and karyotypically abnormal cell lines demonstrating the flexibility of NAT. Availability and implementation: https://github.com/laseaman/4D_Nucleome_Analysis_Toolbox. Contact: indikar@umich.edu.

Nucleome Analysis Reveals Structure-Function Relationships for Colon Cancer.

Chromosomal translocations and aneuploidy are hallmarks of cancer genomes; however, the impact of these aberrations on the nucleome (i.e., nuclear structure and gene expression) is not yet understood. Here, the nucleome of the colorectal cancer cell line HT-29 was analyzed using chromosome conformation capture (Hi-C) to study genome structure, complemented by RNA sequencing (RNA-seq) to determine the consequent changes in genome function. Importantly, translocations and copy number changes were identified at high resolution from Hi-C data and the structure-function relationships present in normal cells were maintained in cancer. In addition, a new copy number-based normalization method for Hi-C data was developed to analyze the effect of chromosomal aberrations on local chromatin structure. The data demonstrate that at the site of translocations, the correlation between chromatin organization and gene expression increases; thus, chromatin accessibility more directly reflects transcription. In addition, the homogeneously staining region of chromosome band 8q24 of HT-29, which includes the MYC oncogene, interacts with various loci throughout the genome and is composed of open chromatin. The methods, described herein, can be applied to the assessment of the nucleome in other cell types with chromosomal aberrations.Implications: Findings show that chromosome conformation capture identifies chromosomal abnormalities at high resolution in cancer cells and that these abnormalities alter the relationship between structure and function. Mol Cancer Res; 15(7); 821-30. ©2017 AACR.

Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers.

Human cells derived for in vitro cultures are conventionally grown as adherent monolayers (2D) which do not resemble natural 3 dimensional (3D) tissue architecture. We examined genome structure with chromosome conformation capture (Hi-C) and gene expression with RNA-seq in fibroblasts derived from human foreskin grown in 2D and 3D conditions. Our combined analysis of Hi-C and RNA-seq data shows a large number of differentially expressed genes between 2D and 3D cells, and these changes are localized in genomic regions that displayed structural changes. We also find a trend of expression in a subset of skin-specific genes in fibroblast cells grown in 3D that resembles those in native tissue.

Periodicity of nuclear morphology in human fibroblasts.

MOTIVATION: Morphology of the cell nucleus has been used as a key indicator of disease state and prognosis, but typically without quantitative rigor. It is also not well understood how nuclear morphology varies with time across different genetic backgrounds in healthy cells. To help answer these questions we measured the size and shape of nuclei in cell-cycle-synchronized primary human fibroblasts from 6 different individuals at 32 time points over a 75 hour period. RESULTS: The nucleus was modeled as an ellipsoid and its dynamics analyzed. Shape and volume changed significantly over this time. Two prominent frequencies were found in the 6 individuals: a 17 hour period consistent with the cell cycle and a 26 hour period. Our findings suggest that the shape of the nucleus changes over time and thus any time-invariant shape property may provide a misleading characterization of cellular populations at different phases of the cell cycle. The proposed methodology provides a general method to analyze morphological change using multiple time points even for non-live-cell experiments.

The Development of a Microbial Challenge Test with Acholeplasma laidlawii To Rate Mycoplasma-Retentive Filters by Filter Manufacturers.

Mycoplasma are bacteria that can penetrate 0.2 and 0.22 µm rated sterilizing-grade filters and even some 0.1 µm rated filters. Primary applications for mycoplasma filtration include large scale mammalian and bacterial cell culture media and serum filtration. The Parenteral Drug Association recognized the absence of standard industry test parameters for testing and classifying 0.1 µm rated filters for mycoplasma clearance and formed a task force to formulate consensus test parameters. The task force established some test parameters by common agreement, based upon general industry practices, without the need for additional testing. However, the culture medium and incubation conditions, for generating test mycoplasma cells, varied from filter company to filter company and was recognized as a serious gap by the task force. Standardization of the culture medium and incubation conditions required collaborative testing in both commercial filter company laboratories and in an Independent laboratory (Table I). The use of consensus test parameters will facilitate the ultimate cross-industry goal of standardization of 0.1 µm filter claims for mycoplasma clearance. However, it is still important to recognize filter performance will depend on the actual conditions of use. Therefore end users should consider, using a risk-based approach, whether process-specific evaluation of filter performance may be warranted for their application. LAY ABSTRACT: Mycoplasma are small bacteria that have the ability to penetrate sterilizing-grade filters. Filtration of large-scale mammalian and bacterial cell culture media is an example of an industry process where effective filtration of mycoplasma is required. The Parenteral Drug Association recognized the absence of industry standard test parameters for evaluating mycoplasma clearance filters by filter manufacturers and formed a task force to formulate such a consensus among manufacturers. The use of standardized test parameters by filter manufacturers, including the preparation of the culture broth, will facilitate the end user's evaluation of the mycoplasma clearance claims provided by filter vendors. However, it is still important to recognize filter performance will depend on the actual conditions of use; therefore end users should consider, using a risk-based approach, whether process-specific evaluation of filter performance may be warranted for their application.