Active Inter-cellular Forces in Collective Cell Motility

The collective behaviour of confluent cell sheets is strongly influenced both by polar forces, arising through cytoskeletal propulsion and by active inter-cellular forces, which are mediated by interactions across cell-cell junctions. We use a phase-field model to explore the interplay between these two contributions and compare the dynamics of a cell sheet when the polarity of the cells aligns to (i) their main axis of elongation, (ii) their velocity, and (iii) when the polarity direction executes a persistent random walk.In all three cases, we observe a sharp transition from a jammed state (where cell rearrangements are strongly suppressed) to a liquid state (where the cells can move freely relative to each other) when either the polar or the inter-cellular forces are increased. In addition, for case (ii) only, we observe an additional dynamical state, flocking (solid or liquid), where the majority of the cells move in the same direction. The flocking state is seen for strong polar forces, but is destroyed as the strength of the inter-cellular activity is increased.Comment: 15 pages,22 figure

Stress-shape misalignment in confluent cell layers

This study investigates the relationship between cell shape and cell-generated stresses in confluent cell layers. Using simultaneous measurements of cell shape orientation and cell-generated contractile forces in MDCK and LP-9 colonies, we report the emergence of correlated, dynamic domains in which misalignment between the directors defined by cell shape and by contractile forces reaches up to 90$^o$, effectively creating extensile domains in a monolayer of contractile cells. To understand this misalignment, we develop a continuum model that decouples the orientation of cell-generated active forces from the orientation of the cell shapes. This challenges the prevailing understanding that cells throughout a tissue create either contractile or extensile forces, and the validity of the usual active nematic models of cell motility where active forces are strictly slaved to cell shape orientation.Comment: 10 pages, 6 figure

ExoMol line lists – XLV. Rovibronic molecular line lists of calcium monohydride (CaH) and magnesium monohydride (MgH)

New molecular line lists for calcium monohydride ({40}^Ca^{1}H) New molecular line lists for calcium monohydride ({40}^Ca^{1}H) and its minor isotopologues ({25}^Mg^{1}H and {26}^Mg^{1}H) are presented. The rotation-vibration-electronic (rovibronic) line lists, named XAB, consider transitions involving the X^{2}Σ^{+}, A{2}^Π, and B/B′ {2}^Σ^{+} electronic states in the 0–30 000 cm^{−1} region (wavelengths λ > 0.33 μm) and are suitable for temperatures up to 5000 K. A comprehensive analysis of the published spectroscopic literature on CaH and MgH is used to obtain new extensive datasets of accurate rovibronic energy levels with measurement uncertainties and consistent quantum number labelling. These datasets are used to produce new spectroscopic models for CaH and MgH, composed of newly empirically-refined potential energy curves and couplings in/between the different electronic states (e.g. spin-orbit, electronic angular momentum, Born-Oppenheimer breakdown, spin-rotation, Λ-doubling) and previously published ab initio transition dipole moment curves. Along with Einstein A coefficients, state lifetimes and Landé g-factors are provided, the latter being particularly useful as CaH and MgH can be used to probe stellar magnetic fields. Computed energy levels have been replaced with the more accurate empirical values (if available) when post-processing the line lists, thus tailoring the line lists to high resolution applications. The XAB line lists are available from the ExoMol database at www.exomol.com and the CDS astronomical database

Pitch-based ribbon-shaped carbon-fiber-reinforced one-dimensional carbon/carbon composites with ultrahigh thermal conductivity

Ribbon-shaped carbon fibers have been prepared from mesophase pitch by melt-spinning, oxidative stabilization and further heat treatment. The internal graphitic layers of ribbon-shaped carbon fibers graphitized at 2800 C show a highly preferred orientation along the longitudinal direction. Parallel stretched and unidirectional arranged ribbon-shaped carbon fibers treated at about 450 C were sprayed with a mesophase pitch powder grout, and then hot-pressed at 500 C and subsequently carbonized and graphitized at various temperatures to produce one-dimensional carbon/carbon (C/C) composite blocks. The shape and microstructural orientation of ribbon fibers have been maintained in the process of hot-pressing and subsequent heat treatments and the main planes of the ribbon fibers are orderly accumulated along the hot-pressing direction. Microstructural analyses indicate that the C/C composite blocks have a typical structural anisotropy derived from the unidirectional arrangement of the highly oriented wide ribbon-shaped fibers in the composite block. The thermal conductivities of the C/C composites along the longitudinal direction of ribbon fibers increase with heat-treatment temperatures. The longitudinal thermal conductivity and thermal diffusivity at room temperature of the C/C composite blocks graphitized at 3100 C are 896 W/m K and 642 mm2/s, respectively.Key Program of Major Research Plan of the National Natural Science Foundation (grant No. 91016003) and the National Natural Science Foundation (grant No. 51372177) of China.http://www.elsevier.com/locate/carbonhb2014ai201

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Cell sorting by active forces in a phase-field model of cell monolayers

Cell sorting, the segregation of cells with different properties into distinct domains, is a key phenomenon in biological processes such as embryogenesis. We use a phase-field model of a confluent cell layer to study the role of activity in cell sorting. We find that a mixture of cells with extensile or contractile dipolar activity, and which are identical apart from their activity, quickly sort into small, elongated patches which then grow slowly in time. We interpret the sorting as driven by the different diffusivity of the extensile and contractile cells, mirroring the ordering of Brownian particles connected to different hot and cold thermostats. We check that the free energy is not changed by either partial or complete sorting, thus confirming that activity can be responsible for the ordering even in the absence of thermodynamic mechanisms