An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada. The results of mycobacterial interspersed repetitive unit-variable-number ...tandem-repeat (MIRU-VNTR) genotyping suggested the outbreak was clonal. Traditional contact tracing did not identify a source. We used whole-genome sequencing and social-network analysis in an effort to describe the outbreak dynamics at a higher resolution.
We sequenced the complete genomes of 32 Mycobacterium tuberculosis outbreak isolates and 4 historical isolates (from the same region but sampled before the outbreak) with matching genotypes, using short-read sequencing. Epidemiologic and genomic data were overlaid on a social network constructed by means of interviews with patients to determine the origins and transmission dynamics of the outbreak.
Whole-genome data revealed two genetically distinct lineages of M. tuberculosis with identical MIRU-VNTR genotypes, suggesting two concomitant outbreaks. Integration of social-network and phylogenetic analyses revealed several transmission events, including those involving "superspreaders." Both lineages descended from a common ancestor and had been detected in the community before the outbreak, suggesting a social, rather than genetic, trigger. Further epidemiologic investigation revealed that the onset of the outbreak coincided with a recorded increase in crack cocaine use in the community.
Through integration of large-scale bacterial whole-genome sequencing and social-network analysis, we show that a socioenvironmental factor--most likely increased crack cocaine use--triggered the simultaneous expansion of two extant lineages of M. tuberculosis that was sustained by key members of a high-risk social network. Genotyping and contact tracing alone did not capture the true dynamics of the outbreak. (Funded by Genome British Columbia and others.).
Compiling an extensive array of information and literature, on the Caligidae, copepods predominantly parasitic on fishes, this book provides a comprehensive generic revision of the ""sea lice"" ...family Caligidae, as well as a phylogenetic analysis of this family and a discussion on the taxonomic status of the genera previously belonging to the Euryphoridae.
Protein expression evolves under greater evolutionary constraint than mRNA levels, and translation efficiency represents a primary determinant of protein levels during stimuli adaptation. This raises ...the question as to the translatome remodelers that titrate protein output from mRNA populations. Here, we uncover a network of RNA-binding proteins (RBPs) that enhances the translation efficiency of glycolytic proteins in cells responding to oxygen deprivation. A system-wide proteomic survey of translational engagement identifies a family of oxygen-regulated RBPs that functions as a switch of glycolytic intensity. Tandem mass tag-pulse SILAC (TMT-pSILAC) and RNA sequencing reveals that each RBP controls a unique but overlapping portfolio of hypoxic responsive proteins. These RBPs collaborate with the hypoxic protein synthesis apparatus, operating as a translation efficiency checkpoint that integrates upstream mRNA signals to activate anaerobic metabolism. This system allows anoxia-resistant animals and mammalian cells to initiate anaerobic glycolysis and survive hypoxia. We suggest that an oxygen-sensitive RBP cluster controls anaerobic metabolism to confer hypoxia tolerance.
Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding ...RNAs (lncRNAs) also define cardiovascular cell type-specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for spliced-transcript endothelial-enriched lncRNA (STEEL) in angiogenic potential, macrovascular/microvascular identity, and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear enriched, and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse ECs. Of interest, STEEL up-regulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL up-regulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.
•A new hoop strain equation for CFST column is developed based on 122 test results.•A theoretical axial stress-strain model with complex 3D stress state is proposed.•Applicability of the proposed ...model verified by 422 test results.•The model to predict the behaviour of confined concrete is verified by test result.
Concrete-filled-steel-tube (CFST) columns are widely adopted in many structures nowadays attributed to the superior behaviour developed by the composite action. However, the composite action cannot be fully developed because of different dilation properties of steel tube and concrete in the elastic stage. Moreover, due to the inelastic outward buckling of steel tube, CFST columns may suffer serious degradation. To overcome these problems, external confinement, such as rings, ties, spirals and FRP wraps have been studied recently and proven experimentally to have potential in improving the uni-axial behaviour of CFST columns. In this paper, an experimental database containing 422 uni-axial compression test results of unconfined and externally confined CFST columns has been assembled. In addition, a theoretical model has been proposed for predicting the uni-axial behaviour of circular CFST columns. This model consists of mainly three components: (1) Constitutive model of confined concrete modified from Attard and Setunge’s actively confined concrete model. (2) Constitutive model of steel tube under complex stress-state using Prandtl-Reuss theory. (3) The interaction among external confinement, steel tube and core concrete based on new a hoop strain equation. The validity of the proposed model has been verified by comparing the predicted results with the experimental database.
A mysterious feature of Crohn’s disease (CD) is the extra-intestinal manifestation of “creeping fat” (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic ...intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
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•Gut bacterial translocation to mesenteric adipose tissue (MAT) naturally occurs•MAT from Crohn’s disease (CD) harbors a bacterial consortium defined by C. innocuum•These bacteria in CD promote restructuring of MAT and formation of “creeping fat”•Creeping fat expansion and fibrosis prevent systemic translocation of gut bacteria
Ha et al. provide evidence that, in humans with inflammatory bowel disease, the phenomenon known as “creeping fat” is a protective response where mesenteric adipose tissue migrates (or “creeps”) to sites of gut barrier dysfunction to prevent systemic dissemination of potentially harmful bacterial antigens that have translocated across the barrier from the gut lumen.
While selective neuronal death has been an influential theme in Huntington's disease (HD), there is now a preponderance of evidence that significant neuronal dysfunction precedes frank neuronal ...death. The best evidence for neuronal dysfunction is the observation that gene expression is altered in HD brain, suggesting that transcriptional dysregulation is a central mechanism. Studies of altered gene expression began with careful observations of postmortem human HD brain and subsequently were accelerated by the development of transgenic mouse models. The application of DNA microarray technology has spurred tremendous progress with respect to the altered transcriptional processes that occur in HD, through gene expression studies of both transgenic mouse models as well as cellular models of HD. Gene expression profiles are remarkably comparable across these models, bolstering the idea that transcriptional signatures reflect an essential feature of disease pathogenesis. Finally, gene expression studies have been applied to human HD, thus not only validating the approach of using model systems, but also solidifying the idea that altered transcription is a key mechanism in HD pathogenesis. In the future, gene expression profiling will be used as a readout in clinical trials aimed at correcting transcriptional dysregulation in Huntington's disease.
Indocyanine green (ICG) is a near-infrared (NIR) contrast agent commonly used for in vivo cardiovascular and eye imaging. For medical diagnosis, ICG is limited by its aqueous instability, ...concentration-dependent aggregation, and rapid degradation. To overcome these limitations, scientists have formulated ICG in various liposomes, which are spherical lipid membrane vesicles with an aqueous core. Some encapsulate ICG, while others mix it with liposomes. There is no clear understanding of lipid–ICG interactions. Therefore, we investigated lipid–ICG interactions by fluorescence and photon correlation spectroscopy. These data were used to design stable and maximally fluorescent liposomal ICG nanoparticles for NIR optical imaging of the lymphatic system. We found that ICG binds to and is incorporated completely and stably into the lipid membrane. At a lipid:ICG molar ratio of 250:1, the maximal fluorescence intensity was detected. ICG incorporated into liposomes enhanced the fluorescence intensity that could be detected across 1.5 cm of muscle tissue, while free ICG only allowed 0.5 cm detection. When administered subcutaneously in mice, lipid-bound ICG in liposomes exhibited a higher intensity, NIR image resolution, and enhanced lymph node and lymphatic vessel visualization. It also reduced the level of fluorescence quenching due to light exposure and degradation in storage. Lipid-bound ICG could provide additional medical diagnostic value with NIR optical imaging for early intervention in cases of lymphatic abnormalities.
Magnetic monopoles may be produced by the Schwinger effect in the strong magnetic fields of peripheral heavy-ion collisions. We review the form of the electromagnetic fields in such collisions and ...calculate from first principles the cross section for monopole pair production. Using the worldline instanton method, we work to all orders in the magnetic charge, and hence are not hampered by the breakdown of perturbation theory. Our result depends on the spacetime inhomogeneity through a single dimensionless parameter, the Keldysh parameter, which is independent of collision energy for a given monopole mass. For realistic heavy-ion collisions, the computational cost of the calculation becomes prohibitive and the finite size of the monopoles needs to be taken into account, and therefore our current results are not applicable to them-we indicate methods of overcoming these limitations, to be addressed in further work. Nonetheless, our results show that the spacetime dependence enhances the production cross section and would therefore lead to stronger monopole mass bounds than in the constant-field case.
The eukaryotic translation initiation factor 4F (eIF4F) has become essentially synonymous with 5′ cap-dependent mRNA translation. Recent studies demonstrate that cells assemble variants of eIF4F to ...produce adaptive, cap-dependent translatomes during physiological conditions that inhibit eIF4F. These findings challenge us to reassess classical perceptions of cellular translational pathways.
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