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"Davies, James"
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The sedated society : the causes and harms of our psychiatric drug epidemic
This edited volume assembles a team of global experts in critical psychopharmacology to address the causes and consequences of our current psychiatric prescribing epidemic. Over 15% of the UK public takes a psychiatric medication on any given day, and the numbers are only set to increase. Placing this figure alongside emerging clinical and scientific data exposing the poor outcomes and harms these medications often cause, this book reveals that their commercial success cannot be explained by their therapeutic efficacy.
Book
Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF
Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that
cis
-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.
Chromosome conformation capture (3 C) techniques have captured largescale 3D genome architecture. Here the authors present their “Tiled-MCC” approach for generation of 3 C data across megabase-scale loci at very high (up to 20 bp) resolution, which allowed them to observe nano-scale chromatin structures and investigate how these structures depend on cohesin and CTCF.
Journal Article
BET inhibition disrupts transcription but retains enhancer-promoter contact
Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.
The role of BRD4 and Mediator in regulating enhancer-promoter interactions is poorly understood. Here the authors find that treatment with BET inhibitors or pharmacological degradation of BRD4 disrupts transcription while having very little effect on enhancer-promoter interactions.
Journal Article
Space, hope, and brutalism : English architecture, 1945-1975
\"This is the first major book to study English architecture between 1945 and 1975 in its entirety. Challenging previous scholarship on the subject and uncovering vast amounts of new material at the boundaries between architectural and social history, Elain Harwood structures the book around building types to reveal why the architecture takes the form it does. Buildings of all budgets and styles are examined, from major universities to the modest cafe;. The book is illustrated with stunning new photography that reveals the logic, aspirations, and beauty of hundreds of buildings throughout England, at the point where many are disappearing or are being mutilated. Space, Hope, and Brutalism offers a convincing and lively overview of a subject and period that fascinates younger scholars and appeals to those who were witnesses to this history. \"-- Provided by publisher.
Book
Multiplexed analysis of chromosome conformation at vastly improved sensitivity
Pooling barcoded 3C libraries and simultaneously capturing interactions at many loci of interest generates reproducible
cis
- and
trans
-interaction maps at high resolution from low amounts of input material. This allows for the comparison of interactions in different cell types using common software designed for differential analysis of sequence count data, rather than requiring software specifically designed for 3C experiments.
Methods for analyzing chromosome conformation in mammalian cells are either low resolution or low throughput and are technically challenging. In next-generation (NG) Capture-C, we have redesigned the Capture-C method to achieve unprecedented levels of sensitivity and reproducibility. NG Capture-C can be used to analyze many genetic loci and samples simultaneously. High-resolution data can be produced with as few as 100,000 cells, and single-nucleotide polymorphisms can be used to generate allele-specific tracks. The method is straightforward to perform and should greatly facilitate the investigation of many questions related to gene regulation as well as the functional dissection of traits examined in genome-wide association studies.
Journal Article
الوجيز في تاريخ الموت
يطرح كتاب (الوجيز في تاريخ الموت) لمؤلفه دوغلاس ج. ديفيس (ترجمة محمود منقذ الهاشمي)، جملة من الأسئلة التي طالما أرقت الإنسان، منذ وجد نفسه في الحياة وحتى اليوم منها : من أين أتى، وإلى أين يذهب بعد الموت، وهل هناك آخرة، ماذا تشبه وكيف عليه التأهب لها ؟ وإذا كانت حياته هي تمام زمنه، كيف له أن يعيشها على أحسن حال، خاصة وهو يعلم أنه سيموت، رغم محاولاته الهرب من الموت ومحاربته له، بكل ما يملك من وسائل الوقاية والعلاج، ذلك لأن الإنسان في الأساس، مسكون (كما يقول مترجم الكتاب) بهاجس تجاوز الموت، ويأمل في أن يستمر في الحياة على نحو ما، ويتألم لفراق من أحبهم، ويخاف من تجربة الموت. ينقسم الكتاب إلى ثمانية فصول، تتناول مسألة الإجابة عن : مشكلة الموت في ملحمة جلجامش، قصة آدم وحواء، يسوع المسيح. كما وتقدم الفصول نظرة عامة إلى : الأديان السماوية والأديان الناشئة في الهند والأساطير اليونانية والرؤى الدنيوية المعاصرة.
Book
Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care
Abstract
Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities.
Journal Article
Defining genome architecture at base-pair resolution
In higher eukaryotes, many genes are regulated by enhancers that are 10
4
–10
6
base pairs (bp) away from the promoter. Enhancers contain transcription-factor-binding sites (which are typically around 7–22 bp), and physical contact between the promoters and enhancers is thought to be required to modulate gene expression. Although chromatin architecture has been mapped extensively at resolutions of 1 kilobase and above; it has not been possible to define physical contacts at the scale of the proteins that determine gene expression. Here we define these interactions in detail using a chromosome conformation capture method (Micro-Capture-C) that enables the physical contacts between different classes of regulatory elements to be determined at base-pair resolution. We find that highly punctate contacts occur between enhancers, promoters and CCCTC-binding factor (CTCF) sites and we show that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters. Our data show that interactions between CTCF sites are increased when active promoters and enhancers are located within the intervening chromatin. This supports a model in which chromatin loop extrusion
1
is dependent on cohesin loading at active promoters and enhancers, which explains the formation of tissue-specific chromatin domains without changes in CTCF binding.
Micro Capture-C allows physical contacts to be determined at base-pair resolution, revealing that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters.
Journal Article