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A Universal Live Cell Barcoding-Platform for Multiplexed Human Single Cell Analysis.
Single-cell barcoding enables the combined processing and acquisition of multiple individual samples as one. This maximizes assay efficiency and eliminates technical variability in both sample preparation and analysis. Remaining challenges are the barcoding of live, unprocessed cells to increase downstream assay performance combined with the flexibility of the approach towards a broad range of cell types. To that end, we developed a novel antibody-based platform that allows the robust barcoding of live human cells for mass cytometry (CyTOF). By targeting both the MHC class I complex (beta-2-microglobulin) and a broadly expressed sodium-potassium ATPase-subunit (CD298) with platinum-conjugated antibodies, human immune cells, stem cells as well as tumor cells could be multiplexed in the same single-cell assay. In addition, we present a novel palladium-based covalent viability reagent compatible with this barcoding strategy. Altogether, this platform enables mass cytometry-based, live-cell barcoding across a multitude of human sample types and provides a scheme for multiplexed barcoding of human single-cell assays in general
Dlx5 Is a Cell Autonomous Regulator of Chondrocyte Hypertrophy in Mice and Functionally Substitutes for Dlx6 during Endochondral Ossification
The axial and appendicular skeleton of vertebrates develops by endochondral ossification, in which skeletogenic tissue is initially cartilaginous and the differentiation of chondrocytes via the hypertrophic pathway precedes the differentiation of osteoblasts and the deposition of a definitive bone matrix. Results from both loss-of-function and misexpression studies have implicated the related homeobox genes Dlx5 and Dlx6 as partially redundant positive regulators of chondrocyte hypertrophy. However, experimental perturbations of Dlx expression have either not been cell type specific or have been done in the context of endogenous Dlx5 expression. Thus, it has not been possible to conclude whether the effects on chondrocyte differentiation are cell autonomous or whether they are mediated by Dlx expression in adjacent tissues, notably the perichondrium. To address this question we first engineered transgenic mice in which Dlx5 expression was specifically restricted to immature and differentiating chondrocytes and not the perichondrium. Col2a1-Dlx5 transgenic embryos and neonates displayed accelerated chondrocyte hypertrophy and mineralization throughout the endochondral skeleton. Furthermore, this transgene specifically rescued defects of chondrocyte differentiation characteristic of the Dlx5/6 null phenotype. Based on these results, we conclude that the role of Dlx5 in the hypertrophic pathway is cell autonomous. We further conclude that Dlx5 and Dlx6 are functionally equivalent in the endochondral skeleton, in that the requirement for Dlx5 and Dlx6 function during chondrocyte hypertrophy can be satisfied with Dlx5 alone
Molecular Epidemiology of Ascariasis: A Global Perspective on the Transmission Dynamics of Ascaris in People and Pigs
Background
The roundworm Ascaris lumbricoides infects 0.8 billion people worldwide, and Ascaris suum infects innumerable pigs across the globe. The extent of natural cross-transmission of Ascaris between pig and human hosts in different geographical settings is unknown, warranting investigation.
Methods
Adult Ascaris organisms were obtained from humans and pigs in Europe, Africa, Asia, and Latin America. Barcodes were assigned to 536 parasites on the basis of sequence analysis of the mitochondrial cytochrome c oxidase I gene. Genotyping of 410 worms was also conducted using a panel of microsatellite markers. Phylogenetic, population genetic, and Bayesian assignment methods were used for analysis.
Results
There was marked genetic segregation between worms originating from human hosts and those originating from pig hosts. However, human Ascaris infections in Europe were of pig origin, and there was evidence of cross-transmission between humans and pigs in Africa. Significant genetic differentiation exists between parasite populations from different countries, villages, and hosts.
Conclusions
In conducting an analysis of variation within Ascaris populations from pig and human hosts across the globe, we demonstrate that cross-transmission takes place in developing and developed countries, contingent upon epidemiological potential and local phylogeography. Our results provide novel insights into the transmission dynamics and speciation of Ascaris worms from humans and pigs that are of importance for control program
An investigation into the feasibility of myoglobin-based single-electron transistors
Myoglobin single-electron transistors were investigated using nanometer- gap
platinum electrodes fabricated by electromigration at cryogenic temperatures.
Apomyoglobin (myoglobin without heme group) was used as a reference. The
results suggest single electron transport is mediated by resonant tunneling
with the electronic and vibrational levels of the heme group in a single
protein. They also represent a proof-of-principle that proteins with redox
centers across nanometer-gap electrodes can be utilized to fabricate
single-electron transistors. The protein orientation and conformation may
significantly affect the conductance of these devices. Future improvements in
device reproducibility and yield will require control of these factors
Force and energy dissipation variations in non-contact atomic force spectroscopy on composite carbon nanotube systems
UHV dynamic force and energy dissipation spectroscopy in non-contact atomic
force microscopy were used to probe specific interactions with composite
systems formed by encapsulating inorganic compounds inside single-walled carbon
nanotubes. It is found that forces due to nano-scale van der Waals interaction
can be made to decrease by combining an Ag core and a carbon nanotube shell in
the Ag@SWNT system. This specific behaviour was attributed to a significantly
different effective dielectric function compared to the individual
constituents, evaluated using a simple core-shell optical model. Energy
dissipation measurements showed that by filling dissipation increases,
explained here by softening of C-C bonds resulting in a more deformable
nanotube cage. Thus, filled and unfilled nanotubes can be discriminated based
on force and dissipation measurements. These findings have two different
implications for potential applications: tuning the effective optical
properties and tuning the interaction force for molecular absorption by
appropriately choosing the filling with respect to the nanotube.Comment: 22 pages, 6 figure
The crisis of democratic culture?
Analysis of whether post truth narratives register as a fundamental threat to democratic cultures in anglo-American context.This piece assesses the risk of disinformation primarily, but not exclusively, in
the Anglo-American context. It unpicks assumptions behind post-truth and
fake news; considers precedents for disinformation and queries the extent of
its novelty. Are these manageable challenges to democratic cultures or a crisis?
It concludes that whatever the terminological tangles, industrialized disinformation
signal threats to the public sphere, threats underscored by historical
events highlighting the vulnerability of democracy. Yet threats to democratic
systems have not deleted their scrutinizing capabilities from below (voters)
and from above (the legislature). Therefore challenges, for all their potency
and potential, have not yet reached crisis
The ‘recovered space’ advection scheme for lowest-order compatible finite element methods
This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We present a new compatible finite element advection scheme for the compressible Euler equations. Unlike the discretisations described in Cotter and Kuzmin (2016) and Shipton et al. (2018), the discretisation uses the lowest-order family of compatible finite element spaces, but still retains second-order numerical accuracy. This scheme obtains this second-order accuracy by first ‘recovering’ the function in higher-order spaces, before using the discontinuous Galerkin advection schemes of Cotter and Kuzmin (2016). As well as describing the scheme, we also present its stability properties and a strategy for ensuring boundedness. We then demonstrate its properties through some numerical tests, before presenting its use within a model solving the compressible Euler equations.Engineering and Physical Science Research Council (EPSRC
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