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Natural Killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface
No full textNatural Killer (NK) cells can kill infected or transformed cells via a lytic immune synapse. Diseased cells may exhibit altered mechanical properties but how this impacts NK cell responsiveness is unknown. We report that human NK cells were stimulated more effectively to secrete granzymes A and B, FasL, granulysin and IFNγ, by stiff (142 kPa) compared to soft (1 kPa) planar substrates. To create surrogate spherical targets of defined stiffness, sodium alginate was used to synthesise soft (9 kPa), medium (34 kPa), or stiff (254 kPa) cell-sized beads, coated with antibodies against activating receptor NKp30 and the integrin LFA-1. Against stiff beads, NK cells showed increased degranulation. Polarisation of the microtubule-organising centre (MTOC) and lytic granules were impaired against soft targets, which instead resulted in the formation of unstable kinapses. Thus, by varying target stiffness to characterise the mechanosensitivity of immune synapses, we identify soft targets as a blind spot in NK cell recognition
Solving Block Low-Rank Linear Systems by LU Factorization is Numerically Stable
No full textBlock low-rank (BLR) matrices possess a blockwise low-rank property that can be exploited to reduce the complexity of numerical linear algebra algorithms. The impact of these low-rank approximations on the numerical stability of the algorithms in floating-point arithmetic has not previously been analyzed. We present rounding error analysis for the solution of a linear system by LU factorization of BLR matrices. Assuming that a stable pivoting scheme is used, we prove backward stability: the relative backward error is bounded by a modest constant times e, where the low-rank threshold e is the parameter controlling the accuracy of the blockwise low-rank approximations. In addition to this key result, our analysis offers three new insights into the numerical behavior of BLR algorithms. First, we compare the use of a global or local low-rank threshold and find that a global one should be preferred. Second, we show that performing intermediate recompressions during the factorization can significantly reduce its cost without compromising numerical stability. Third, we consider different BLR factorization variants and determine the update–compress–factor (UCF) variant to be the best. Tests on a wide range of matrices from various real-life applications show that the predictions from the analysis are realized in practice
Ivosidenib: an investigational drug for the treatment of biliary tract cancer
No full textIntroduction: Biliary tract cancer (including cholangiocarcinoma and gallbladder cancer) is rare and associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable targets and in this review we focus on isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; currently approved for the treatment of acute myeloid leukaemia, it has also been studied in patients with advanced cholangiocarcinoma. Areas covered: The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of ivosidenib in advanced cholangiocarcinoma are discussed. Expert opinion: Ivosidenib is well-tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p<0.0001) as well as a trend towards increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potentially-therapeutic targets and thereby improve the prognosis of patients with these cancers
Characterizing Dislocation Loops in Irradiated Zr alloys by X-ray Line Profile Analysis of Diffraction Patterns with Satellites
No full textIn this work we extend the convolutional multiple whole profile (CMWP) line profile analysis (LPA) procedure to determine the total dislocation density and character of irradiation-induced dislocation loops in commercial polycrystalline Zr specimens. Zr alloys are widely used in the nuclear industry as fuel cladding materials in which irradiation-induced point defects evolve into dislocation loops. LPA has long been established as a powerful tool to determine the density and nature of lattice defects in plastically deformed materials. The CMWP LPA procedure is based on the Krivoglaz-Wilkens theory in which the dislocation structure is characterized by the total dislocation density and the dislocation arrangement parameter, ρ and M. In commercial Zr alloys irradiation-induced dislocation loops broaden peak profiles mainly in the tail regions and occasionally generate small satellites next to the Bragg peaks. In this work we have solved the two challenges in powder diffraction patterns of irradiated Zr alloys: (a) we have made determination of the M values from the long tail regions of peaks unequivocal and (b) have fitted satellites separately, using physically well-established principles, in order to exclude them from the dislocation determination process. Referring to the theory of heterogeneous dislocation distributions we have justified determination of the total dislocation density from the main peaks free from satellites. We characterize the dislocation loop structure by the total dislocation density of loops and the M parameter correlated to the dipole character of dislocation loops. The extended CMWP procedure is applied to determine the total dislocation density, the dipolecharacter of dislocation loops and the fractions of <a> and <c> type loops in proton or neutron irradiated polycrystalline Zr alloys used in the nuclear energy industry
A polarization census of bright pulsars using the Ultra-Wideband Receiver on the Parkes radio telescope
No full textWe present high signal-to-noise, full polarization pulse profiles for 40 bright, ‘slowly’-rotating (non-recycled) pulsars using the new Ultra-Wideband Low-frequency (UWL; 704–4032 MHz) receiver on the Parkes radio telescope. We obtain updated and accurate interstellar medium parameters towards these pulsars (dispersion measures and Faraday rotation measures), and reveal Faraday dispersion towards PSR J1721–3532 caused by interstellar scattering. We find general trends in the pulse profiles including decreasing fractional linear polarization and increasing degree of circular polarization with increasing frequency, consistent with previous studies, while also revealing new features and frequency evolution. This demonstrates results that can be obtained using UWL monitoring observations of slow pulsars, which are valuable for improving our understanding of pulsar emission and the intervening interstellar medium. The calibrated data products are publicly available
Moded and Continuous Abstract State Machines
No full textIn view of the increasing importance of cyber-physical systems, and of their correct design, the Abstract State Machine (ASM) framework is extended to include continuously varying quantities as well as the conventional discretely changing ones. This opens the door to the more faithful modelling of many scenarios where digital systems have to interact with the continuously varying physical world. Transitions in the extended framework are thus either moded (catering for discontinuously changing quantities), or pliant (catering for smoothly changing quantities). An operational semantics is provided, first for monolithic systems, and this is then extended to give a semantics for systems consisting of several distinct subsystems. This allows each subsystem to undergo its own subsystem-specific mode and pliant transitions. Refinement is elaborated in the extended context for both monolithic and composed systems. The formalism is illustrated using an example of a bouncing tennis ball
Can autocracy promote literacy? evidence from a cultural alignment success story
No full textDo countries with less democratic forms of government necessarily have lower literacy rates as a consequence? Using a random sample of more than 9000 individuals from military archives in 20th century Portugal, we show that 20-year old males were 50% more likely to end up literate under a nondemocratic regime than under a more democratic one. Our results are robust to controlling for a host of factors including economic growth, the disease environment, and regional fixed-effects. We argue for a political economy and cultural explanation for the relative success of the authoritarian regime in promoting basic education
“A veto for the government”:The Money Message as a foil to new legislation
No full textVeto players hold the capacity to decline a choice being made, making them powerful actors within legislative systems. During 2016-2020, Ireland was governed by a minority government, reliant on confidence and supply votes from other parliamentarians, thus it did not hold a veto during parliamentary votes. However, if the independent Bills Office deemed a ‘Money Message’ would be necessary for a Private Members’ Bill (PMB), even if it had achieved majority support in the Dáil, then the government could refuse to grant one, returning veto status to the minority government. To date, research has not provided a comprehensive overview of the PMBs blocked, nor examined in detail the cases that were high-profile. Via a nested analysis, we code 79 PMBs, and complement our analysis through interviews with parliamentarians whose bills were blocked. We identify eleven policy themes in the PMBs that were blocked, demonstrating that vetoing via the Money Message was a widespread phenomenon. Next, we conduct a small-n analysis of the application of Money Messages across a variety of bills. Our analysis provides the first comprehensive examination of a procedure that holds lasting implications for the legislative process, perceptions of democracy, and executive dominance over minor parties in Ireland
Reduced microbial stability in the active layer is associated with carbon loss under alpine permafrost degradation
No full textClimate warming has led to extensive permafrost degradation, potentially inducing massive soil carbon loss. However, microbially mediated mechanisms responsible for carbon loss from the active layer in degraded permafrost remain unclear. Thus, we investigated how soil microbial communities in the active layer respond to permafrost degradation and influence carbon storage in alpine ecosystems of the Qinghai-Tibet Plateau. Our results reveal that severe degradation of permafrost increased bacterial and fungal dissimilarities and reduced bacterial and archaeal community richness. Microbial community stability also declined, as evidenced by increased microbial community sensitivity to environmental change and a prevalence of destabilizing properties of microbial networks. It was estimated that the increase in microbial dissimilarity was associated with amplified soil organic carbon loss in severely-degraded permafrost. Overall, our study implies significant changes in microbial diversity and stability of the active layer in alpine ecosystems under permafrost degradation, with potential implications for carbon-climate feedbacks
Expectation-driven novelty effects in episodic memory
No full textNovel and unexpected stimuli are often prioritised in memory, given their inherent salience. Nevertheless, not all forms of novelty show such an enhancement effect. Here, we discuss the role expectation plays in modulating the way novelty affects memory processes, circuits, and subsequent performance. We first review independent effects of expectation on memory, and then consider how different types of novelty are characterised by expectation. We argue that different types of novelty defined by expectation implicate differential neurotransmission in memory formation brain regions and may also result in the creation of different types of memory. Contextual novelty, which is unexpected by definition, is often associated with better recollection, supported by dopaminergic-hippocampal interactions. On the other hand, expected stimulus novelty is supported by engagement of medial temporal cortices, as well as the hippocampus, through cholinergic modulation. Furthermore, when expected stimulus novelty results in enhanced memory, it is predominantly driven by familiarity. The literature reviewed here highlights the complexity of novelty-sensitive memory systems, the distinction between types of novelty, and how they are differentially affected by expectancy.</p