One of the most innovative and brilliant philosophers of his generation, but largely neglected until he was brought to public attention by Gilles Deleuze, Gilbert Simondon presents a challenge to ...nearly every category and method of traditional philosophy. ' Psychic and Collective Individuation ' is undoubtedly his most important work and its influence, clearly felt in Stiegler and DeLanda, has continued to grow. David Scott provides the first full introduction to this work, which will inspire as well as instruct philosophers working in Continental thought, philosophy of science, social theory and political philosophy. He introduces Simondon's challenging text by clarifying its complex terminology and structure through a chapter-by-chapter commentary. By placing Simondon and the book in their historical context, Scott invites a dialogue with thinkers including Bergson, Deleuze, Heidegger, Sartre, Merleau-Ponty and Negri, and explains Simondon's relevance to current discussions about biopolitics and post-Nietzschean ethics.
The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event triggering the amyloidogenic pathway—a key step in Alzheimer’s disease (AD) pathology. However, as both ...APP/BACE-1 are highly expressed in brain, mechanisms precluding their unabated convergence are unclear. Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that after synthesis via the secretory pathway, dendritic APP/BACE-1-containing vesicles are largely segregated in physiologic states. While BACE-1 is sorted into acidic recycling endosomes, APP is conveyed in Golgi-derived vesicles. However, upon activity induction—a known trigger of the amyloidogenic pathway—APP is routed into BACE-1-positive recycling endosomes via a clathrin-dependent mechanism. A partitioning/convergence of APP/BACE-1 vesicles is also apparent in control/AD brains, respectively. Considering BACE-1 is optimally active in an acidic environment, our experiments suggest that neurons have evolved trafficking strategies that normally limit APP/BACE-1 proximity and also uncover a pathway routing APP into BACE-1-containing organelles, triggering amyloidogenesis.
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•APP and BACE-1 are sorted into distinct neuronal organelles•APP and BACE-1 converge upon induction of neuronal activity•Convergence of APP with BACE-1 is dependent upon endocytosis of APP•APP and BACE1 converge in neuronal recycling endosomes
APP cleavage by the enzyme BACE is a key event in Alzheimer’s pathology. But what prevents unabated APP cleavage and relentless pathology? Das et al. report that APP/BACE are sorted into distinct organelles—inhibiting APP cleavage—but converge upon triggers favoring such cleavage.
This edited book, as you can see from its title, is about learning, or at least about the concept and practice of learning. The contributors to this volume are focusing on two meta-concepts, ...knowledge and learning, on the relationship between the two, and the way these can be framed in epistemic, social, political and economic terms. Knowledge and learning, as meta-concepts, are positioned in various networks or constellations of meaning, principally: the antecedents of the concepts, their relations to other relevant concepts, and the way the concepts are used in the lifeworld. In this book the various authors explore a number of important concepts that are relevant to the idea of learning. These are meta-concepts such as epistemology, inferential role semantics, phenomenology, rationality, thinking, hermeneutics, critical realism and pragmatism, and meso-concepts such as probability, woman, training, assessment, education, system, race, friendship, Bildung, curriculum, ecology and pedagogy. Like David Scott's first volume of On Learning, this collection focusing on philosophy, concepts and practices is a response to empiricist and positivist conceptions of knowledge. It challenges detheorised and reductionist ideas of learning that have filtered through to the management of our schools, colleges and universities; over-simplified messages about learning, knowledge, curriculum and assessment; and fostered the denial that values are central to understanding how we live and how we should live - the normative dimension to social policy and social theorising. This book is also an attempt at a Bildungstheorie.
The Sociology of Refugee Migration FitzGerald, David Scott; Arar, Rawan
Annual review of sociology,
07/2018, Volume:
44, Issue:
1
Journal Article
Peer reviewed
Open access
Theorization in the sociology of migration and the field of refugee studies has been retarded by a path-dependent division that we argue should be broken down by greater mutual engagement. Excavating ...the construction of the refugee category reveals how unwarranted assumptions shape contemporary disputes about the scale of refugee crises, appropriate policy responses, and suitable research tools. Empirical studies of how violence interacts with economic and other factors shaping mobility offer lessons for both fields. Adapting existing theories that may not appear immediately applicable, such as household economy approaches, helps explain refugees' decision-making processes. At a macro level, world systems theory sheds light on the interactive policies around refugees across states of origin, mass hosting, asylum, transit, and resettlement. Finally, focusing on the integration of refugees in the Global South reveals a pattern that poses major challenges to theories of assimilation and citizenship developed in settler states of the Global North.
Targeted genome editing technologies have enabled a broad range of research and medical applications. The Cas9 nuclease from the microbial CRISPR-Cas system is targeted to specific genomic loci by a ...20 nt guide sequence, which can tolerate certain mismatches to the DNA target and thereby promote undesired off-target mutagenesis. Here, we describe an approach that combines a Cas9 nickase mutant with paired guide RNAs to introduce targeted double-strand breaks. Because individual nicks in the genome are repaired with high fidelity, simultaneous nicking via appropriately offset guide RNAs is required for double-stranded breaks and extends the number of specifically recognized bases for target cleavage. We demonstrate that using paired nicking can reduce off-target activity by 50- to 1,500-fold in cell lines and to facilitate gene knockout in mouse zygotes without sacrificing on-target cleavage efficiency. This versatile strategy enables a wide variety of genome editing applications that require high specificity.
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•Cas9 nickase can facilitate targeted DNA double-strand break using two guide RNAs•Double nicking of DNA reduces off-target mutagenesis by 50- to 1,000-fold•Multiplex nicking stimulates homology directed repair, microdeletion, and insertion•Double nicking provides efficient modification of mouse zygotes
The RNA-guided Cas9 nuclease can tolerate certain mismatches to the DNA target and can thereby promote undesired off-target mutagenesis. A “double nicking” strategy has been developed to significantly reduce off-target activity in cell lines and to facilitate efficient gene knockout in mouse zygotes, enabling genome editing applications with higher levels of specificity.
CRISPR-Cas genome-editing methods hold immense potential as therapeutic tools to fix disease-causing mutations at the level of DNA. In contrast to typical drug development strategies aimed at targets ...that are highly conserved among individual patients, treatment at the genomic level must contend with substantial inter-individual natural genetic variation. Here we analyze the recently released ExAC and 1000 Genomes data sets to determine how human genetic variation impacts target choice for Cas endonucleases in the context of therapeutic genome editing. We find that this genetic variation confounds the target sites of certain Cas endonucleases more than others, and we provide a compendium of guide RNAs predicted to have high efficacy in diverse patient populations. For further analysis, we focus on 12 therapeutically relevant genes and consider how genetic variation affects off-target candidates for these loci. Our analysis suggests that, in large populations of individuals, most candidate off-target sites will be rare, underscoring the need for prescreening of patients through whole-genome sequencing to ensure safety. This information can be integrated with empirical methods for guide RNA selection into a framework for designing CRISPR-based therapeutics that maximizes efficacy and safety across patient populations.
Abstract Objective The assessment of health-related quality-of-life (HRQoL) in rheumatoid arthritis (RA) is becoming increasingly common in both research and clinical practice. One of the most widely ...used tools for measuring HRQoL is the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). We conducted a systematic review examining the impact of RA on HRQoL, measured through the SF-36. Methods MEDLINE and Embase were searched for observational studies reporting mean and standard deviation scores for each domain of the SF-36 in adult RA patients. Studies were reviewed in accordance with PRISMA guidelines, and a random-effects meta-analysis was performed. Results In total, 31 studies were eligible for inclusion in the meta-analysis, including 22,335 patients. Meta-analyses found that pooled mean HRQoL score for the SF-36 physical component summary was 34.1 (95% CI: 22.0–46.1) and mental component summary was 45.6 (95% CI: 30.3–60.8). Increased age was associated with reduced physical function and physical component summary (PCS) scores but improved mental health and mental component summary (MCS) scores. Female gender was associated with improved scores on role physical, bodily pain and PCS but reduced mental health and MCS scores. Longer disease duration was associated with improved MCS. Patients with RA have a substantially reduced HRQoL in comparison to both other physical illnesses and in comparison to normative datasets from UK and USA populations. Conclusions RA has a substantial impact on HRQoL. This supports recent NICE guidelines stipulating that RA patients should be regularly assessed for the impact their disease has on HRQoL and appropriate management provided.
Healthy individuals are generally immunologically tolerant to proteins derived from one's self (termed self proteins). However, patients with monogenic clotting disorders, like hemophilia A (HemA), ...lack central tolerance to the absent self protein. Thus, when exposed to replacement therapy, such as procoagulant factor VIII, they may mount an immune response against the very self protein that is missing. In the current issue of the JCI, Becker-Gotot, Meissner, et al. present data on a possible mechanism for tolerance to factor VIII in healthy individuals and the immune response in patients, involving a role of PD-1 and T regulatory cells. The findings suggest that treatment with PD-1- and PD-1L-specific reagents may induce tolerance in patients with autoimmune disease, especially those with HemA who also possess inhibiting antibodies.
Bacterial class 2 CRISPR-Cas systems utilize a single RNA-guided protein effector to mitigate viral infection. We aggregated genomic data from multiple sources and constructed an expanded database of ...predicted class 2 CRISPR-Cas systems. A search for novel RNA-targeting systems identified subtype VI-D, encoding dual HEPN domain-containing Cas13d effectors and putative WYL-domain-containing accessory proteins (WYL1 and WYL-b1 through WYL-b5). The median size of Cas13d proteins is 190 to 300 aa smaller than that of Cas13a–Cas13c. Despite their small size, Cas13d orthologs from Eubacterium siraeum (Es) and Ruminococcus sp. (Rsp) are active in both CRISPR RNA processing and targeting, as well as collateral RNA cleavage, with no target-flanking sequence requirements. The RspWYL1 protein stimulates RNA cleavage by both EsCas13d and RspCas13d, demonstrating a common regulatory mechanism for divergent Cas13d orthologs. The small size, minimal targeting constraints, and modular regulation of Cas13d effectors further expands the CRISPR toolkit for RNA manipulation and detection.
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•Type VI-D is a CRISPR-Cas system with a Cas13d effector and a WYL domain accessory•Cas13d is an RNA-guided RNase approximately 20% smaller than Cas13a–Cas13c effectors•WYL1 positively modulates Cas13d target and collateral RNase activity•Cas13d has minimal sequence and secondary structure requirements for targeting
Compiling an expanded database of predicted class 2 CRISPR-Cas systems, Yan et al. identify and characterize subtype VI-D. Cas13d is an RNA-guided RNase effector with polyphyletic WYL-domain accessory proteins. One WYL1 ortholog enhances activity of divergent Cas13d orthologs. The small effector size and modular enhancement further expand RNA modification capabilities.
B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus ...on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
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