Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico

Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico

Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment

Coherent vortex dynamics in a strongly-interacting superfluid on a silicon chip

Two-dimensional superfluidity and quantum turbulence are directly connected to the microscopic dynamics of quantized vortices. However, surface effects have prevented direct observations of coherent vortex dynamics in strongly-interacting two-dimensional systems. Here, we overcome this challenge by confining a two-dimensional droplet of superfluid helium at microscale on the atomically-smooth surface of a silicon chip. An on-chip optical microcavity allows laser-initiation of vortex clusters and nondestructive observation of their decay in a single shot. Coherent dynamics dominate, with thermal vortex diffusion suppressed by six orders-of-magnitude. This establishes a new on-chip platform to study emergent phenomena in strongly-interacting superfluids, test astrophysical dynamics such as those in the superfluid core of neutron stars in the laboratory, and construct quantum technologies such as precision inertial sensors.Comment: Main text - 12 pages, 4 figures. Supplementary materials - 25 pages, 13 figure

Current-voltage characteristics of diluted Josephson-junction arrays: scaling behavior at current and percolation threshold

Dynamical simulations and scaling arguments are used to study the current-voltage (IV) characteristics of a two-dimensional model of resistively shunted Josephson-junction arrays in presence of percolative disorder, at zero external field. Two different limits of the Josephson-coupling concentration $p$ are considered, where $p_c$ is the percolation threshold. For $p$ $>$ $p_c$ and zero temperature, the IV curves show power-law behavior above a disorder dependent critical current. The power-law behavior and critical exponents are consistent with a simple scaling analysis. At $p_c$ and finite temperature $T$, the results show the scaling behavior of a T=0 superconducting transition. The resistance is linear but vanishes for decreasing $T$ with an apparent exponential behavior. Crossover to non-linearity appears at currents proportional to $$, with a thermal-correlation length exponent $\nu_T$ consistent with the corresponding value for the diluted XY model at $p_c$.Comment: Revtex, 9 postscript pages, to appear in Phys. Rev.

Inferring PDZ Domain Multi-Mutant Binding Preferences from Single-Mutant Data

Many important cellular protein interactions are mediated by peptide recognition domains. The ability to predict a domain's binding specificity directly from its primary sequence is essential to understanding the complexity of protein-protein interaction networks. One such recognition domain is the PDZ domain, functioning in scaffold proteins that facilitate formation of signaling networks. Predicting the PDZ domain's binding specificity was a part of the DREAM4 Peptide Recognition Domain challenge, the goal of which was to describe, as position weight matrices, the specificity profiles of five multi-mutant ERBB2IP-1 domains. We developed a method that derives multi-mutant binding preferences by generalizing the effects of single point mutations on the wild type domain's binding specificities. Our approach, trained on publicly available ERBB2IP-1 single-mutant phage display data, combined linear regression-based prediction for ligand positions whose specificity is determined by few PDZ positions, and single-mutant position weight matrix averaging for all other ligand columns. The success of our method as the winning entry of the DREAM4 competition, as well as its superior performance over a general PDZ-ligand binding model, demonstrates the advantages of training a model on a well-selected domain-specific data set

Large-scale shock-ionized and photo-ionized gas in M83: the impact of star formation

We investigate the ionization structure of the nebular gas in M83 using the line diagnostic diagram, [O III](5007 \degA)/H{\beta} vs. [S II](6716 \deg A+6731 \deg A)/H{\alpha} with the newly available narrowband images from the Wide Field Camera 3 (WFC3) of the Hubble Space Telescope (HST). We produce the diagnostic diagram on a pixel-by-pixel (0.2" x 0.2") basis and compare it with several photo- and shock-ionization models. For the photo-ionized gas, we observe a gradual increase of the log([O III]/H{\beta}) ratios from the center to the spiral arm, consistent with the metallicity gradient, as the H II regions go from super solar abundance to roughly solar abundance from the center out. Using the diagnostic diagram, we separate the photo-ionized from the shock-ionized component of the gas. We find that the shock-ionized H{\alpha} emission ranges from ~2% to about 15-33% of the total, depending on the separation criteria used. An interesting feature in the diagnostic diagram is an horizontal distribution around log([O III]/H{\beta}) ~ 0. This feature is well fit by a shock-ionization model with 2.0 Z\odot metallicity and shock velocities in the range of 250 km/s to 350 km/s. A low velocity shock component, < 200 km/s, is also detected, and is spatially located at the boundary between the outer ring and the spiral arm. The low velocity shock component can be due to : 1) supernova remnants located nearby, 2) dynamical interaction between the outer ring and the spiral arm, 3) abnormal line ratios from extreme local dust extinction. The current data do not enable us to distinguish among those three possible interpretations. Our main conclusion is that, even at the HST resolution, the shocked gas represents a small fraction of the total ionized gas emission at less than 33% of the total. However, it accounts for virtually all of the mechanical energy produced by the central starburst in M83.Comment: Accepted for publication in ApJ. aastex preprint 12pt, 21 pages, 13 figure

Biomechanical risk factors for carpal tunnel syndrome: a pooled study of 2474 workers

BACKGROUND: Between 2001 and 2010, five research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries and collected detailed subject-level exposure information with follow-up of symptoms, electrophysiological measures and job changes. OBJECTIVE: This analysis examined the associations between workplace biomechanical factors and incidence of dominant-hand CTS, adjusting for personal risk factors. METHODS: 2474 participants, without CTS or possible polyneuropathy at enrolment, were followed up to 6.5 years (5102 person-years). Individual workplace exposure measures of the dominant hand were collected for each task and included force, repetition, duty cycle and posture. Task exposures were combined across the workweek using time-weighted averaging to estimate job-level exposures. CTS case-criteria were based on symptoms and results of electrophysiological testing. HRs were estimated using Cox proportional hazard models. RESULTS: After adjustment for covariates, analyst (HR=2.17; 95% CI 1.38 to 3.43) and worker (HR=2.08; 95% CI 1.31 to 3.39) estimated peak hand force, forceful repetition rate (HR=1.84; 95% CI 1.19 to 2.86) and per cent time spent (eg, duty cycle) in forceful hand exertions (HR=2.05; 95% CI 1.34 to 3.15) were associated with increased risk of incident CTS. Associations were not observed between total hand repetition rate, per cent duration of all hand exertions, or wrist posture and incident CTS. CONCLUSIONS: In this prospective multicentre study of production and service workers, measures of exposure to forceful hand exertion were associated with incident CTS after controlling for important covariates. These findings may influence the design of workplace safety programmes for preventing work-related CTS

General population job exposure matrix applied to a pooled study of prevalent carpal tunnel syndrome

A job exposure matrix may be useful for the study of biomechanical workplace risk factors when individual-level exposure data are unavailable. We used job title–based exposure data from a public data source to construct a job exposure matrix and test exposure-response relationships with prevalent carpal tunnel syndrome (CTS). Exposures of repetitive motion and force from the Occupational Information Network were assigned to 3,452 active workers from several industries, enrolled between 2001 and 2008 from 6 studies. Repetitive motion and force exposures were combined into high/high, high/low, and low/low exposure groupings in each of 4 multivariable logistic regression models, adjusted for personal factors. Although force measures alone were not independent predictors of CTS in these data, strong associations between combined physical exposures of force and repetition and CTS were observed in all models. Consistent with previous literature, this report shows that workers with high force/high repetition jobs had the highest prevalence of CTS (odds ratio = 2.14–2.95) followed by intermediate values (odds ratio = 1.09–2.27) in mixed exposed jobs relative to the lowest exposed workers. This study supports the use of a general population job exposure matrix to estimate workplace physical exposures in epidemiologic studies of musculoskeletal disorders when measures of individual exposures are unavailable

Personal and workplace psychosocial risk factors for carpal tunnel syndrome: a pooled study cohort

BACKGROUND: Between 2001 and 2010, six research groups conducted coordinated multiyear, prospective studies of carpal tunnel syndrome (CTS) incidence in US workers from various industries and collected detailed subject-level exposure information with follow-up symptom, physical examination, electrophysiological measures and job changes. OBJECTIVE: This analysis of the pooled cohort examined the incidence of dominant-hand CTS in relation to demographic characteristics and estimated associations with occupational psychosocial factors and years worked, adjusting for confounding by personal risk factors. METHODS: 3515 participants, without baseline CTS, were followed-up to 7 years. Case criteria included symptoms and an electrodiagnostic study consistent with CTS. Adjusted HRs were estimated in Cox proportional hazard models. Workplace biomechanical factors were collected but not evaluated in this analysis. RESULTS: Women were at elevated risk for CTS (HR=1.30; 95% CI 0.98 to 1.72), and the incidence of CTS increased linearly with both age and body mass index (BMI) over most of the observed range. High job strain increased risk (HR=1.86; 95% CI 1.11 to 3.14), and social support was protective (HR=0.54; 95% CI 0.31 to 0.95). There was an inverse relationship with years worked among recent hires with the highest incidence in the first 3.5 years of work (HR=3.08; 95% CI 1.55 to 6.12). CONCLUSIONS: Personal factors associated with an increased risk of developing CTS were BMI, age and being a woman. Workplace risk factors were high job strain, while social support was protective. The inverse relationship between CTS incidence and years worked among recent hires suggests the presence of a healthy worker survivor effect in the cohort