Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death

Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination

Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape

Slow cross-symmetry phase relaxation in complex collisions

We discuss the effect of slow phase relaxation and the spin off-diagonal $S$-matrix correlations on the cross section energy oscillations and the time evolution of the highly excited intermediate systems formed in complex collisions. Such deformed intermediate complexes with strongly overlapping resonances can be formed in heavy ion collisions, bimolecular chemical reactions and atomic cluster collisions. The effects of quasiperiodic energy dependence of the cross sections, coherent rotation of the hyperdeformed $\simeq (3:1)$ intermediate complex, Schr\"odinger cat states and quantum-classical transition are studied for $^{24}$Mg+$^{28}$Si heavy ion scattering.Comment: 10 pages including 2 color ps figures. To be published in Physics of Atomic Nuclei (Yadernaya fizika

Community response in disasters: an ecological learning framework

Natural disasters are frequently exacerbated by anthropogenic mechanisms and have social and political consequences for communities. The role of community learning in disasters is seen to be increasingly important. However, the ways in which such learning unfolds in a disaster can differ substantially from case to case. This article uses a comparative case study methodology to examine catastrophes and major disasters from five countries (Japan, New Zealand, the UK, the USA and Germany) to consider how community learning and adaptation occurs. An ecological model of learning is considered, where community learning is of small loop (adaptive, incremental, experimental) type or large loop (paradigm changing) type. Using this model, we consider that there are three types of community learning that occur in disasters (navigation, organization, reframing). The type of community learning that actually develops in a disaster depends upon a range of social factors such as stress and trauma, civic innovation and coercion

The ‘state of exception’ and disaster education: a multilevel conceptual framework with implications for social justice

The term ‘state of exception’ has been used by Italian political theorist Giorgio Agamben to explain the ways in which emergencies, crises and disasters are used by governments to suspend legal processes. In this paper, we innovatively apply Agamben’s theory to the way in which countries prepare and educate the population for various types of emergencies. We focus on two main aspects of Agamben’s work: first, the paradoxical nature of the state of exception, as both a transient and a permanent part of governance. Second, it is a ‘liminal’ concept expressing the limits of law and where ‘law’ meets ‘not-law’. We consider the relationship between laws related to disasters and emergencies, and case studies of the ways in which three countries (England, Germany and Japan) educate their populations for crisis and disaster. In England, we consider how emergency powers have been orientated around the protection of the Critical National Infrastructure and how this has produced localised ‘states of exception’ and, relatedly, pedagogical anomalies. In Germany, we consider the way in which laws related to disaster and civil protection, and the nature of volunteering for civil protection, produce exceptional spaces for non-German bodies. In Japan, we consider the debate around the absence of emergency powers and relate this to Japanese non-exceptional disaster education for natural disasters. Applying Agamben’s work, we conclude by developing a new, multilevel empirical framework for analysing disaster education with implications for social justice

Induction of plasminogen activator inhibitor type-1 (PAI-1) by hypoxia and irradiation in human head and neck carcinoma cell lines

Contains fulltext : 53187.pdf ( ) (Open Access)BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) often contain highly radioresistant hypoxic regions, nonetheless, radiotherapy is a common treatment modality for these tumours. Reoxygenation during fractionated radiotherapy is desired to render these hypoxic tumour regions more radiosensitive. Hypoxia additionally leads to up-regulation of PAI-1, a protein involved in tumour progression and an established prognostic marker for poor outcome. However, the impact of reoxygenation and radiation on PAI-1 levels is not yet clear. Therefore, we investigated the kinetics of PAI-1 expression and secretion after hypoxia and reoxygenation, and determined the influence of ionizing radiation on PAI-1 levels in the two human SCCHN cell lines, BHY and FaDu. METHODS: HIF-1alpha immunoblot was used to visualize the degree of hypoxia in the two cell lines. Cellular PAI-1 expression was investigated by immunofluorescence microscopy. ELISA was used to quantify relative changes in PAI-1 expression (cell lysates) and secretion (cell culture supernatants) in response to various lengths (2-4 h) of hypoxic exposure (< 0.66% O2), reoxygenation (24 h, 20% O2), and radiation (0, 2, 5 and 10 Gy). RESULTS: HIF-1alpha expression was induced between 2 and 24 h of hypoxic exposure. Intracellular PAI-1 expression was significantly increased in BHY and FaDu cells as early as 4 h after hypoxic exposure. A significant induction in secreted PAI-1 was seen after 12 to 24 h (BHY) and 8 to 24 h (FaDu) hypoxia, as compared to the normoxic control. A 24 h reoxygenation period caused significantly less PAI-1 secretion than a 24 h hypoxia period in FaDu cells. Irradiation led to an up-regulation of PAI-1 expression and secretion in both, BHY and FaDu cells. CONCLUSION: Our data suggest that both, short-term (approximately 4-8 h) and long-term (approximately 20-24 h) hypoxic exposure could increase PAI-1 levels in SCCHN in vivo. Importantly, radiation itself could lead to PAI-1 up-regulation in head and neck tumours, whereas reoxygenation of hypoxic tumour cells during fractionated radiotherapy could counteract the increased PAI-1 levels

Preparing for disaster: a comparative analysis of education for critical infrastructure collapse

This article explores policy approaches to educating populations for potential critical infrastructure collapse in five different countries: the UK, the US, Germany, Japan and New Zealand. ‘Critical infrastructure’ is not always easy to define, and indeed is defined slightly differently across countries – it includes entities vital to life, such as utilities (water, energy), transportation systems and communications, and may also include social and cultural infrastructure. The article is a mapping exercise of different approaches to critical infrastructure protection and preparedness education by the five countries. The exercise facilitates a comparison of the countries and enables us to identify distinctive characteristics of each country’s approach. We argue that contrary to what most scholars of security have argued, these national approaches diverge greatly, suggesting that they are shaped more by internal politics and culture than by global approaches

Storage of Correlated Patterns in Standard and Bistable Purkinje Cell Models

The cerebellum has long been considered to undergo supervised learning, with climbing fibers acting as a ‘teaching’ or ‘error’ signal. Purkinje cells (PCs), the sole output of the cerebellar cortex, have been considered as analogs of perceptrons storing input/output associations. In support of this hypothesis, a recent study found that the distribution of synaptic weights of a perceptron at maximal capacity is in striking agreement with experimental data in adult rats. However, the calculation was performed using random uncorrelated inputs and outputs. This is a clearly unrealistic assumption since sensory inputs and motor outputs carry a substantial degree of temporal correlations. In this paper, we consider a binary output neuron with a large number of inputs, which is required to store associations between temporally correlated sequences of binary inputs and outputs, modelled as Markov chains. Storage capacity is found to increase with both input and output correlations, and diverges in the limit where both go to unity. We also investigate the capacity of a bistable output unit, since PCs have been shown to be bistable in some experimental conditions. Bistability is shown to enhance storage capacity whenever the output correlation is stronger than the input correlation. Distribution of synaptic weights at maximal capacity is shown to be independent on correlations, and is also unaffected by the presence of bistability

The militarisation of English schools: Troops to Teaching and the implications for Initial Teacher Education and race equality

This article considers the implications of the Troops to Teaching (TtT) programme, to be introduced in England in autumn 2013, for Initial Teacher Education (ITE) and race equality. TtT will fast-track ex-armed service members to teach in schools, without necessarily the requirement of a university degree. Employing theories of white supremacy, and Althusser’s (1971) concept of Ideological and Repressive State Apparatus, I argue that this initiative both stems from, and contributes to, a system of social privilege and oppression in education. Despite appearing to be aimed at all young people, the planned TtT initiative is actually aimed at poor and racially subordinated youth. This is likely to further entrench polarisation in a system which already provides two tier educational provision: TtT will be a programme for the inner-city disadvantaged, whilst wealthier, whiter schools will mostly continue to get highly qualified teachers. Moreover, TtT contributes to a wider devaluing of current ITE; ITE itself is rendered virtually irrelevant, as it seems TtT teachers will not be subject specialists, rather will be expected to provide military-style discipline, the skills for which they will be expected to bring with them. More sinister, I argue that TtT is part of the wider militarisation of education. This military-industrial-education complex seeks to contain and police young people who are marginalised along lines of race and class, and contributes to a wider move to increase ideological support for foreign wars - both aims ultimately in the service of neoliberal objectives which will feed social inequalities

Nonspecific synaptic plasticity improves the recognition of sparse patterns degraded by local noise

Safaryan, K. et al. Nonspecific synaptic plasticity improves the recognition of sparse patterns degraded by local noise. Sci. Rep. 7, 46550; doi: 10.1038/srep46550 (2017). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2017.Many forms of synaptic plasticity require the local production of volatile or rapidly diffusing substances such as nitric oxide. The nonspecific plasticity these neuromodulators may induce at neighboring non-active synapses is thought to be detrimental for the specificity of memory storage. We show here that memory retrieval may benefit from this non-specific plasticity when the applied sparse binary input patterns are degraded by local noise. Simulations of a biophysically realistic model of a cerebellar Purkinje cell in a pattern recognition task show that, in the absence of noise, leakage of plasticity to adjacent synapses degrades the recognition of sparse static patterns. However, above a local noise level of 20 %, the model with nonspecific plasticity outperforms the standard, specific model. The gain in performance is greatest when the spatial distribution of noise in the input matches the range of diffusion-induced plasticity. Hence non-specific plasticity may offer a benefit in noisy environments or when the pressure to generalize is strong.Peer reviewe