Monitoring dynamics of single-cell gene expression over multiple cell cycles

Recent progress in reconstructing gene regulatory networks has established a framework for a quantitative description of the dynamics of many important cellular processes. Such a description will require novel experimental techniques that enable the generation of time-series data for the governing regulatory proteins in a large number of individual living cells. Here, we utilize microfabrication to construct a Tesla microchemostat that permits single-cell fluorescence imaging of gene expression over many cellular generations. The device is used to capture and constrain asymmetrically dividing or motile cells within a trapping region and to deliver nutrients and regulate the cellular population within this region. We illustrate the operation of the microchemostat with Saccharomyces cerevisiae and explore the evolution of single-cell gene expression and cycle time as a function of generation. Our findings highlight the importance of novel assays for quantifying the dynamics of gene expression and cellular growth, and establish a methodology for exploring the effects of gene expression on long-term processes such as cellular aging

A high-Q metasurface signal isolator for 1.5T surface coil magnetic resonance imaging on the go

The combination of surface coils and metamaterials remarkably enhance magnetic resonance imaging (MRI) performance for significant local staging flexibility. However, due to the coupling in between, impeded signal-to-noise ratio (SNR) and low-contrast resolution, further hamper the future growth in clinical MRI. In this paper, we propose a high-Q metasurface decoupling isolator fueled by topological LC loops for 1.5T surface coil MRI system, increasing the magnetic field up to fivefold at 63.8 MHz. We have employed a polarization conversion mechanism to effectively eliminate the coupling between the MRI metamaterial and the radio frequency (RF) surface transmitter-receiver coils. Furthermore, a high-Q metasurface isolator was achieved by taking advantage of bound states in the continuum (BIC) for extremely high-field MRI and spectroscopy. An equivalent physical model of the miniaturized metasurface design was put forward through LC circuit analysis. This study opens up a promising route for the easy-to-use and portable surface coil MRI scanners

Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A

Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (Kiapp of 7±2.4 µM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (Kiapp of 3.8±0.8 µM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors

International standards for fetal brain structures based on serial ultrasound measurements from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.

OBJECTIVE: To create prescriptive growth standards for five fetal brain structures, measured by ultrasound, from healthy, well-nourished women, at low risk of impaired fetal growth and poor perinatal outcomes, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. METHODS: This was a complementary analysis of a large, population-based, multicentre, longitudinal study. We measured, in planes reconstructed from 3-dimensional (3D) ultrasound volumes of the fetal head at different time points in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle (AV), atrium of the posterior ventricle (PV) and cisterna magna (CM). The sample analysed was randomly selected from the overall FGLS population, ensuring an equal distribution amongst the eight diverse participating sites and of 3D ultrasound volumes across pregnancy (range: 15 - 36 weeks' gestation). Fractional polynomials were used to the construct standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. RESULTS: From the entire FGLS cohort of 4321 women, 451 (10.4%) were randomly selected. After exclusions, 3D ultrasound volumes from 442 fetuses born without congenital malformations were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures showed increasing size with gestation and increasing variability for the POF, SF, PV and CM. The 3rd , 5th , 50th , 95th and 97th smoothed centile are presented. The 5th centile of POF and SF were 2.8 and 4.3 at 22 weeks and 4.2 and 9.4mm at 32 weeks respectively. The 95th centile of PV and CM were 8.5 and 7.4 at 22 weeks and 8.5 and 9.4mm at 32 weeks respectively. CONCLUSIONS: We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcomes. We recommend these as international standards for the assessment of measurements obtained by ultrasound from fetal brain structures

Positive words carry less information than negative words

We show that the frequency of word use is not only determined by the word length \cite{Zipf1935} and the average information content \cite{Piantadosi2011}, but also by its emotional content. We have analyzed three established lexica of affective word usage in English, German, and Spanish, to verify that these lexica have a neutral, unbiased, emotional content. Taking into account the frequency of word usage, we find that words with a positive emotional content are more frequently used. This lends support to Pollyanna hypothesis \cite{Boucher1969} that there should be a positive bias in human expression. We also find that negative words contain more information than positive words, as the informativeness of a word increases uniformly with its valence decrease. Our findings support earlier conjectures about (i) the relation between word frequency and information content, and (ii) the impact of positive emotions on communication and social links.Comment: 16 pages, 3 figures, 3 table

Mixed cytomegalovirus genotypes in HIV-positive mothers show compartmentalization and distinct patterns of transmission to infants.

Cytomegalovirus (CMV) is the commonest cause of congenital infection and particularly so among infants born to HIV-infected women. Studies of congenital CMV infection (cCMVi) pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection

Higgsing M2 to D2 with gravity: N=6 chiral supergravity from topologically gauged ABJM theory

We present the higgsing of three-dimensional N=6 superconformal ABJM type theories coupled to conformal supergravity, so called topologically gauged ABJM theory, thus providing a gravitational extension of previous work on the relation between N M2 and N D2-branes. The resulting N=6 supergravity theory appears at a chiral point similar to that of three-dimensional chiral gravity introduced recently by Li, Song and Strominger, but with the opposite sign for the Ricci scalar term in the lagrangian. We identify the supersymmetry in the broken phase as a particular linear combination of the supersymmetry and special conformal supersymmetry in the original topologically gauged ABJM theory. We also discuss the higgsing procedure in detail paying special attention to the role played by the U(1) factors in the original ABJM model and the U(1) introduced in the topological gauging.Comment: 53 pages, Late

Mixed cytomegalovirus genotypes in HIV positive mothers show compartmentalization and distinct patterns of transmission to infants

Cytomegalovirus (CMV) is the commonest cause of congenital infection (cCMVi) and particularly so among infants born to HIV-infected women. Studies of cCMVi pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue-tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection

Field theories with anisotropic scaling in 2D, solitons and the microscopic entropy of asymptotically Lifshitz black holes

Field theories with anisotropic scaling in 1+1 dimensions are considered. It is shown that the isomorphism between Lifshitz algebras with dynamical exponents z and 1/z naturally leads to a duality between low and high temperature regimes. Assuming the existence of gap in the spectrum, this duality allows to obtain a precise formula for the asymptotic growth of the number of states with a fixed energy which depends on z and the energy of the ground state, and reduces to the Cardy formula for z=1. The holographic realization of the duality can be naturally inferred from the fact that Euclidean Lifshitz spaces in three dimensions with dynamical exponents and characteristic lengths given by z, l, and 1/z, l/z, respectively, are diffeomorphic. The semiclassical entropy of black holes with Lifshitz asymptotics can then be recovered from the generalization of Cardy formula, where the ground state corresponds to a soliton. An explicit example is provided by the existence of a purely gravitational soliton solution for BHT massive gravity, which precisely has the required energy that reproduces the entropy of the analytic asymptotically Lifshitz black hole with z=3. Remarkably, neither the asymptotic symmetries nor central charges were explicitly used in order to obtain these results.Comment: 17 pages, no figures, references corrected and update