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Validating the inspired sinewave technique to measure lung heterogeneity compared to atelectasis & over-distended volume in computed tomography images
No full textOn the mortality problem: From multiplicative matrix equations to linear recurrence sequences and beyond
No full textWe consider the following variant of the mortality problem: given k×k matrices A1, A2, . . . , At, do there exist t nonnegative integers m1, m2, . . . , mt such that the product A1m1 A2m2· · · Atmt is equal to the zero matrix? It is known that this problem is decidable when t ≤ 2 for matrices over algebraic numbers but becomes undecidable for sufficiently large t and k, even for integral matrices.
In this paper, we prove the first decidability results for t > 2. We show as one of our central results that for t = 3 this problem in any dimension is Turing equivalent to the well-known Skolem problem for linear recurrence sequences. Our proof relies on the primary decomposition theorem for matrices. Up to now, this result has not been used to prove decidability results about matrix semigroups. As a corollary we obtain that the above problem is decidable for t = 3 and k ≤ 3 for matrices over algebraic numbers and for t = 3 and k = 4 for
matrices over real algebraic numbers. Another consequence is that the set of triples (m1, m2, m3) for which the equation A1m1 A2m2 A3m3 equals the zero matrix is equal to a finite union of direct products of semilinear sets.
For t = 4 we show that the solution set can be non-semilinear, and thus it seems unlikely that there is a direct connection to the Skolem problem. However we prove that the problem is still decidable for upper-triangular 2 × 2 rational matrices by employing powerful tools from transcendence theory such as Baker’s theorem and S-unit equations
A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic etiology with obesity
No full textLung function is a heritable complex phenotype with obesity being one of its important risk factors. However, the knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWAS in other populations are lacking.
We included 100 285 subjects from China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS were performed on FEV1, FVC, FEV1/FVC in CKB. We then performed genome-wide cross-trait analysis between the lung function and obesity traits (body mass index [BMI], BMI-adjusted waist-to-hip ratio, and BMI-adjusted waist circumference) to investigate the shared genetic effects in CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in CKB and its interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with CKB using 457 756 subjects from UK Biobank (UKB) for replication and investigation of ancestry specific effect.
We identified 9 genome-wide significant novel loci for FEV1, 6 for FVC and 3 for FEV1/FVC in CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important pathways, including cell proliferation, embryo and tissue development. Mendelian randomisation analysis suggested significant negative causal effect of BMI on FEV1 and on FVC in both CKB and UKB. Lung function PRSs significantly modified the effect of change-in-BMI on change-in-lung function during an average follow-up of 8 years.
This large-scale GWAS of lung function identified novel loci and shared genetic etiology between lung function and obesity. Change-in-BMI might affect change-in-lung function differently according to a subject's polygenic background. These findings may open new avenue for the development of molecular-targeted therapies for obesity and lung function improvement
Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition
No full textArtemis (SNM1C/DCLRE1C) is an endonuclease that plays a key role in development of B- and T-lymphocytes and in dsDNA break repair by non-homologous end-joining (NHEJ). Artemis is phosphorylated by DNA-PKcs and acts to open DNA hairpin intermediates generated during V(D)J and class-switch recombination. Artemis deficiency leads to congenital radiosensitive severe acquired immune deficiency (RS-SCID). Artemis belongs to a superfamily of nucleases containing metallo-β-lactamase (MBL) and β-CASP (CPSF-Artemis-SNM1-Pso2) domains. We present crystal structures of the catalytic domain of wildtype and variant forms of Artemis, including one causing RS-SCID Omenn syndrome. The catalytic domain of the Artemis has similar endonuclease activity to the phosphorylated full-length protein. Our structures help explain the predominantly endonucleolytic activity of Artemis, which contrasts with the predominantly exonuclease activity of the closely related SNM1A and SNM1B MBL fold nucleases. The structures reveal a second metal binding site in its β-CASP domain unique to Artemis, which is amenable to inhibition by compounds including ebselen. By combining our structural data with that from a recently reported Artemis structure, we were able model the interaction of Artemis with DNA substrates. The structures, including one of Artemis with the cephalosporin ceftriaxone, will help enable the rational development of selective SNM1 nuclease inhibitors
Classical observables from coherent-spin amplitudes
No full textThe quantum field-theoretic approach to classical observables due to Kosower, Maybee and O’Connell provides a rigorous pathway from on-shell scattering amplitudes to classical perturbation theory. In this paper, we promote this formalism to describe general classical spinning objects by using coherent spin states. Our approach is fully covariant with respect to the massive little group SU(2) and is therefore completely synergistic with the massive spinor-helicity formalism. We apply this approach to classical two-body scattering due gravitational interaction. Starting from the coherent-spin elastic-scattering amplitude, we derive the classical impulse and spin kick observables to first post-Minkowskian order but to all orders in the angular momenta of the massive spinning objects. From the same amplitude, we also extract an effective two-body Hamiltonian, which can be used beyond the scattering setting. As a cross-check, we rederive the classical observables in the center-of-mass frame by integrating the Hamiltonian equations of motion to the leading order in Newton’s constant
Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children
No full textThe evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on infections in healthy adults based on single timepoint data. Here, we analysed the within-host evolution of 82 longitudinally-sampled individuals, mostly young children, infected with A/H1N1pdm09 or A/H3N2 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous minority variants were more prevalent than synonymous ones. For A/H3N2 viruses in young children, early infection was dominated by purifying selection. As these infections progressed, nonsynonymous variants typically increased in frequency even when within-host virus titres decreased. Unlike the short-lived infections of adults where de novo within-host variants are rare, longer infections in young children allow for the maintenance of virus diversity via mutation-selection balance creating potentially important opportunities for within-host virus evolution
KCNE4-dependent functional consequences of Kv1.3-related leukocyte physiology
No full textThe voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. The regulatory subunit KCNE4 acts as an ancillary peptide of Kv1.3, modulates K+ currents and controls channel abundance at the cell surface. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Thus, KCNE4 is crucial for Ca2+-dependent Kv1.3-related leukocyte functions. To better understand the role of KCNE4 in the regulation of the immune system, we manipulated its expression in various leukocyte cell lines. Jurkat T lymphocytes exhibit low KCNE4 levels, whereas CY15 dendritic cells, a model of professional antigen-presenting cells, robustly express KCNE4. When the cellular KCNE4 abundance was increased in T cells, the interaction between KCNE4 and Kv1.3 affected important T cell physiological features, such as channel rearrangement in the immunological synapse, cell growth, apoptosis and activation, as indicated by decreased IL-2 production. Conversely, ablation of KCNE4 in dendritic cells augmented proliferation. Furthermore, the LPS-dependent activation of CY15 cells, which induced Kv1.3 but not KCNE4, increased the Kv1.3-KCNE4 ratio and increased the expression of free Kv1.3 without KCNE4 interaction. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions
Rapid encoding of musical tones discovered in whole-brain connectivity
No full textInformation encoding has received a wide neuroscientific attention, but the underlying rapid spatiotemporal brain dynamics remain largely unknown. Here, we investigated the rapid brain mechanisms for encoding of sounds forming a complex temporal sequence. Specifically, we used magnetoencephalography (MEG) to record the brain activity of 68 participants while they listened to a highly structured musical prelude. Functional connectivity analyses performed using phase synchronisation and graph theoretical measures showed a large network of brain areas recruited during encoding of sounds, comprising primary and secondary auditory cortices, frontal operculum, insula, hippocampus and basal ganglia. Moreover, our results highlighted the rapid transition of brain activity from primary auditory cortex to higher order association areas including insula and superior temporal pole within a whole-brain network, occurring during the first 220 ms of the encoding process. Further, we discovered that individual differences along cognitive abilities and musicianship modulated the degree centrality of the brain areas implicated in the encoding process. Indeed, participants with higher musical expertise presented a stronger centrality of superior temporal gyrus and insula, while individuals with high working memory abilities showed a stronger centrality of frontal operculum. In conclusion, our study revealed the rapid unfolding of brain network dynamics responsible for the encoding of sounds and their relationship with individual differences, showing a complex picture which extends beyond the well-known involvement of auditory areas. Indeed, our results expanded our understanding of the general mechanisms underlying auditory pattern encoding in the human brain
Using practical work: strategies to avoid closing down practice
No full textPractical work has long been regarded as a fundamental part of science education, despite ongoing concerns about its use in lessons, the ways in which it is assessed and the tendency for these ways to close down practice. Project Calibrate, a partnership between researchers at AQA and the University of Oxford Department of Education, has worked with secondary science teachers to explore the use of a new framework to design new GCSE-level written assessments of practical work and how these might guide classroom practice. Findings show that this approach can indeed open up classroom practice and some specific suggestions for ITE and CPD are discussed
Comparative analysis of continuum angiogenesis models
No full textAlthough discrete approaches are increasingly employed to model biological phenomena, it remains unclear how complex, population-level behaviours in such frameworks arise from the rules used to represent interactions between individuals. Discrete-to-continuum approaches, which are used to derive systems of coarse-grained equations describing the mean-field dynamics of a microscopic model, can provide insight into such emergent behaviour. Coarse-grained models often contain nonlinear terms that depend on the microscopic rules of the discrete framework, however, and such nonlinearities can make a model difficult to mathematically analyse. By contrast, models developed using phenomenological approaches are typically easier to investigate but have a more obscure connection to the underlying microscopic system. To our knowledge, there has been little work done to compare solutions of phenomenological and coarse-grained models. Here we address this problem in the context of angiogenesis (the creation of new blood vessels from existing vasculature). We compare asymptotic solutions of a classical, phenomenological “snail-trail” model for angiogenesis to solutions of a nonlinear system of partial differential equations (PDEs) derived via a systematic coarse-graining procedure (Pillay et al. in Phys Rev E 95(1):012410, 2017. https://doi.org/10.1103/PhysRevE.95.012410). For distinguished parameter regimes corresponding to chemotaxis-dominated cell movement and low branching rates, both continuum models reduce at leading order to identical PDEs within the domain interior. Numerical and analytical results confirm that pointwise differences between solutions to the two continuum models are small if these conditions hold, and demonstrate how perturbation methods can be used to determine when a phenomenological model provides a good approximation to a more detailed coarse-grained system for the same biological process