Quantifying Gene Regulatory Networks

<p>\abstract</p><p>Transcription and translation describe the flow of genetic information from DNA to mRNA to protein. Recent studies show that at a single cell level, these processes are stochastic, which results in the variation of the number of mRNA and proteins even under identical environmental conditions. Because the number of mRNA and protein in each single cell are actually very small, these variations can be crucial for cellular function in diverse contexts, such as development, stress response, immunological and nervous system function. Most studies examine the origin and effects of stochastic gene expression using computer simulations. My goal is to develop a theoretical framework to study activity-dependent gene expression using simplified models that capture essential features. </p><p>I have examined the dynamics of stochastic gene regulation in three contexts. First, I examine how fluctuations in promoter accessibility lead to "bursty" transcription, during which genes are turned "on" or "off" stochastically. I describe a mathematical formalism to represent bursty gene expression in a coarse-grained manner as a Markov process and derive a master equation for the time evolution of the probability distribution of the number of mRNA molecules. This allows us to examine how transcript number responds to time varying stimuli. This model forms a basic building block for understanding the signal transmission and noise of the transcription process to time varying inputs as would be sensed by cells in dynamic environments. In addition to synthesis, gene expression is subject to additional modes of regulation. One such mechanism that controls transcript numbers is by microRNAs (miRNAs), which pair with target mRNAs to repress protein production following transcription. Although hundreds of miRNAs have been identified in mammalian genomes, the function of miRNA-based repression in the context of gene regulation networks still remains unclear. I explore the functional roles of feedback regulation by miRNAs and show that protein fluctuations strongly depend on the mode of miRNA-mediated repression. I discuss the functional implications of protein fluctuations arising from miRNA-mediated repression on gene regulatory networks. Finally, I examine the impact of fluctuations on alternative splicing, which is a major source for proteomic complexity in higher eukaryotes. Although the proteins regulating alternative splicing have been extensively studied, little is known about how noise arising from the stochastic nature of alternative splicing contributes to the entire gene expression process. I explore the functional roles and noise properties of alternative splicing, focusing on the case of exon skipping and intron retention. I show that while the overall counts of the mRNAs of the two isoforms are independent and Poisson distributed, diffusion and binding of the splicing factors contributes to the variance in the abundance of the isoforms. </p><p>Noise in gene expression may be of particular relevance in the nervous system. Environmental stimuli drive the rapid remodeling of neural circuitry in part by inducing the activation of genes to make proteins that modify neuronal excitability and connectivity, ultimately influencing higher order brain function. Finally, I examine the implications of our studies for activity dependent gene expression in the nervous system.</p>Dissertatio

Two novel variations in LRP2 cause Donnai-Barrow syndrome in a Chinese family with severe early-onset high myopia

Donnai-Barrow syndrome (DBS) is a rare autosomal recessive disorder caused by mutation in the low density lipoprotein receptor-related protein 2 gene (LRP2). Defects in this protein may lead to clinical multiple organ malformations by affecting the development of organs such as the nervous system, eyes, ears, and kidneys. Although some variations on LRP2 have been found to be associated with DBS, early diagnosis and prevention of patients with atypical DBS remains a challenge for many physicians because of their clinical heterogeneity. The objective of this study is to explore the association between the clinical presentation and the genotype of a DBS patient who was initially diagnosed with early-onset high myopia (eoHM) from a healthy Chinese family. To this end, we tested the patient of this family via whole exome sequencing and further verified the results among other family members by Sanger sequencing. Comprehensive ophthalmic tests as well as other systemic examinations were also performed on participants with various genotypes. Genetic assessment revealed that two novel variations in LRP2, a de novo missense variation (c.9032G&gt;A; p.Arg3011Lys) and a novel splicing variation (c.2909-2A&gt;T) inherited from the father, were both carried by the proband in this family, and they are strongly associated with the typical clinical features of DBS patients. Therefore, in this paper we are the first to report two novel compound heterozygous variations in LPR2 causing DBS. Our study extends the genotypic spectrums for LPR2-DBS and better assists physicians in predicting, diagnosing, and conducting gene therapy for DBS

Accuracy of triage strategies for human papillomavirus DNA-positive women in low-resource settings: A cross-sectional study in China

CareHPV is a human papillomavirus (HPV) DNA test for low-resource settings (LRS). This study assesses optimum triage strategies for careHPV-positive women in LRS

Seroprevalence of Human Papillomavirus Types 6, 11, 16 and 18 in Chinese Women

Abstract Background Human papillomavirus (HPV) seroprevalence data have not previously been reported for different geographical regions of China. This study investigated the cross-sectional seroprevalence of antibodies to HPV 6, 11, 16, and 18 virus-like particles in Chinese women. Methods Population-based samples of women were enrolled from 2006 to 2007 in 3 rural and 2 urban areas of China. Each consenting woman completed a questionnaire and provided a blood sample. Serum antibodies were detected using a competitive Luminex immunoassay that measures antibodies to type-specific, neutralizing epitopes on the virus-like particles. Results A total of 4,731 women (median age 35, age range 14-54) were included, of which 4,211 were sexually active women (median age 37) and 520 virgins (median age 18). Low risk HPV 6 was the most common serotype detected (7.3%), followed by HPV 16 (5.6%), HPV 11 (2.9%), and HPV 18 (1.9%). Overall HPV seroprevalence to any type was significantly higher among sexually active women (15.8%) than virgins (2.5%) (P = 0.005). Overall seroprevalence among sexually active women gradually increased with age. Women from rural regions had significantly lower overall seroprevalence (Odds Ratio (OR) = 0.7; 95% CI: 0.6-0.9, versus metropolitan regions, P  = 4 partners versus 1 partner, P < 0.001). Wives were at higher risk of seropositivity for HPV 16/18/6/11 when reporting having a husband who had an extramarital sexual relationship (OR = 2.0; 95% CI: 1.6-2.5, versus those whose husbands having no such relationship, P < 0.001). There was a strong association between HPV 16 seropositivity and presence of high-grade cervical lesions (OR = 6.5; 95% CI: 3.7-11.4, versus normal cervix, P < 0.001). Conclusions HPV seroprevalence differed significantly by age, geography, and sexual behavior within China, which all should be considered when implementing an optimal prophylactic HPV vaccination program in China

Collective colony growth is optimized by branching pattern formation in Pseudomonas aeruginosa

Abstract Branching pattern formation is common in many microbes. Extensive studies have focused on addressing how such patterns emerge from local cell–cell and cell–environment interactions. However, little is known about whether and to what extent these patterns play a physiological role. Here, we consider the colonization of bacteria as an optimization problem to find the colony patterns that maximize colony growth efficiency under different environmental conditions. We demonstrate that Pseudomonas aeruginosa colonies develop branching patterns with characteristics comparable to the prediction of modeling; for example, colonies form thin branches in a nutrient‐poor environment. Hence, the formation of branching patterns represents an optimal strategy for the growth of Pseudomonas aeruginosa colonies. The quantitative relationship between colony patterns and growth conditions enables us to develop a coarse‐grained model to predict diverse colony patterns under more complex conditions, which we validated experimentally. Our results offer new insights into branching pattern formation as a problem‐solving social behavior in microbes and enable fast and accurate predictions of complex spatial patterns in branching colonies

Figure S1 from Trend in Cervical Cancer Incidence and Mortality Rates in China, 2006–2030: A Bayesian Age-Period-Cohort Modeling Study

Figure S1 shows trends for incidence cases during 2006−2016 and predicted from 2017 to 2030 in China.</p

Novel TiO2 Nanoparticles/Polysulfone Composite Hollow Microspheres for Photocatalytic Degradation

Nanosized titanium oxide (TiO2) material is a promising photocatalyst for the degradation of organic pollutants, whereas the difficulty of its recycling hinders its practical application. Herein, we reported the preparation of a novel titanium oxide/polysulfone (TiNPs/PSF) composite hollow microspheres by the combination of Pickering emulsification and the solvent evaporation technique and their application for the photodegradation of methyl blue (MB). P25 TiO2 nanoparticles dispersed on the surface of PSF microspheres. The porosity, density and photoactivity of the TiNPs/PSF composite microsphere are influenced by the TiO2 loading amount. The composite microsphere showed good methyl blue (MB) removal ability. Compared with TiO2 P25, and PSF, a much higher MB adsorption speed was observed for TiNPs/PSF microspheres benefited from their porous structure and the electrostatic attractions between the MB+ and the negatively charged PSF materials, and showed good degradation efficiency. For TiNPs/PSF composite microsphere with density close to 1, a 100% MB removal (10 mg L&minus;1) within 120 min at a catalyst loading of 2.5 g L&minus;1 can be obtained under both stirring and static condition, due to well dispersing of TiO2 particles on the microsphere surface and its stable suspending in water. For the non-suspended TiNPs/PSF composite microsphere with density bigger than 1, the 100% MB removal can be only obtained under stirring condition. The removal efficiency of MB for the composite microspheres retained 96.5%, even after 20 cycles. Moreover, this composite microsphere also showed high MB removal ability at acidic condition. The high catalysis efficiency, excellent reusability and good stability make this kind of TiNPs/PSF composite microsphere a promising photocatalyst for the water organic pollution treatment