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\"Every day, children and adolescents worldwide return to the educational setting having sustained a traumatic brain injury (TBI). The possible negative consequences of TBI range from mild to severe and include neurological, cognitive, emotional, social, and behavioral difficulties. Within the school setting, the negative effects of TBI tend to persist or worsen over time, often resulting in academic and social difficulties that require formal and informal educational assistance and support. School psychologists and other educational professionals are well-positioned to help ensure students with TBI receive this assistance and support. Working with Traumatic Brain Injury in Schools is a comprehensive practitioner-oriented guide to effective school-based services for students who have experienced a TBI. It is primarily written for school-based professionals who have limited or no neurological or neuropsychological training; however, it contains educational information that is useful to professionals with extensive knowledge in neurology and/or neuropsychology. This book is also written for parents and guardians of students with TBI because of their integral role in the transition, school-based assessment, and school-based intervention processes. Chapter topics include: basic brain anatomy and physiology; head injury and severity level classifications; biomechanics of injury; injury recovery and rehabilitation; neurological, cognitive, emotional, behavioral, social, and academic consequences; understanding community-based assessment findings; a framework for school-based assessment (TBI-SNNAP); school-based psychoeducational report writing, and school-based interventions; monitoring pharmacological interventions; and prevention. An accompanying website includes handouts, sample reports, and training templates to assist professionals in recognizing and responding to students with TBI\"-- Provided by publisher.

Key Points RNA interference (RNAi) is a powerful approach for reducing expression of endogenously expressed proteins for biological applications, or targeting the expression of pathological proteins for therapy. Several delivery methods are available to achieve RNAi in ex vivo and in vivo settings for therapeutic results. The development of RNAi-based therapeutics has advanced sufficiently to allow human clinical trials to begin. Here we outline the broad range of cell-, tissue- and disease-specific approaches under investigation for RNAi therapeutics. The barriers posed by certain cells and tissues are described, as are issues with off-target silencing. RNA interference can elicit specific gene silencing and so holds great potential for treating infectious or genetic diseases. Several small-RNA-based therapies have now reached clinical trials, but further work is still needed to improve delivery and efficacy. RNA interference (RNAi) is a powerful approach for reducing expression of endogenously expressed proteins. It is widely used for biological applications and is being harnessed to silence mRNAs encoding pathogenic proteins for therapy. Various methods — including delivering RNA oligonucleotides and expressing RNAi triggers from viral vectors — have been developed for successful RNAi in cell culture and in vivo. Recently, RNAi-based gene silencing approaches have been demonstrated in humans, and ongoing clinical trials hold promise for treating fatal disorders or providing alternatives to traditional small molecule therapies. Here we describe the broad range of approaches to achieve targeted gene silencing for therapy, discuss important considerations when developing RNAi triggers for use in humans, and review the current status of clinical trials.

\"Entrepreneurship for the Rest of Us reveals the best practices of the most successful entrepreneurs, those who are adept at continually innovating and seeing opportunity where others do not\"-- Provided by publisher.

In a porcine cystic fibrosis model, lack of cystic fibrosis transmembrane conductance regulator (CFTR) is shown to result in acidification of airway surface liquid (ASL), and this decrease in pH reduces the ability of ASL to kill bacteria; the findings directly link loss of the CFTR anion channel to impaired defence against bacterial infection. Lung susceptibility to bacterial infection in cystic fibrosis The discovery of a link between cystic fibrosis and mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene has stimulated two decades of extensive research. As a result, the genetic, functional and cellular aspects of CFTR are well known. But despite these advances, it has proved impossible to relate the pathogenesis of bacterial lung infection, the major cause of morbidity and mortality in the disease, to the basic physiological abnormality — the loss of CFTR anion channels. The experiments reported here show that without CFTR, when airway epithelial HCO 3 secretion is defective, the pH of the airway surface liquid falls and inhibits antimicrobial function. This impairs the killing of bacteria that enter the lungs. Reducing the pH of the airway surface layer diminished bactericidal activity in wild-type pigs, whereas increasing the pH restored antimicrobial activity in pigs lacking CFTR . These findings link CFTR mutations to defective bacterial eradication, and suggest that increasing the pH of the airway surface liquid might prevent the initial infection in patients with cystic fibrosis. Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene 1 . Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain 2 , 3 , 4 , 5 , 6 . To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease 7 , 8 . At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria 8 . Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo , when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO 3 − transport 9 , 10 , 11 , 12 , 13 . Without CFTR, airway epithelial HCO 3 − secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.

The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer’s disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer’s disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain.

Key Points Histone variants replace canonical histones to carry out diverse roles in replication, transcription and heterochromatin formation, all of which are mediated by the activity of chaperones, chromatin remodellers and histone-modifying enzymes. Some chaperones have evolved to distinguish between histone variants and canonical histones and direct them into specialized assembly pathways, whereas other chaperones process variants and canonical histones similarly. The MCM2 subunit of the replication helicase does not distinguish between canonical H3 and its variants, and may pass different H3 variants as well as post-translationally modified H3 from the front to the back of the replication fork. By contrast, new nucleosomes comprising canonical histones are deposited behind the fork by the chaperone chromatin assembly factor 1 (CAF1), which excludes H3 variants. H2A.Z has a conserved role in transcription initiation, which nevertheless varies between organisms and contexts. H2A.Z is found flanking promoters and in some enhancers and can recruit RNA polymerase II, but is then evicted by the transcription machinery. Other H2A variants — H2A.B and macroH2A — can occupy specific promoters in specific cell types. H2A.B, which wraps only ∼120 bp of DNA, appears to facilitate transcription, whereas macroH2a may reinforce active or repressed expression states. H3.3 has high turnover rates at regulatory elements such as enhancers. HIRA deposits H3.3 in gene bodies to replace nucleosomes evicted during transcription, whereas ATRX–DAXX (alpha thalassemia mental retardation syndrome X-linked–death domain associated protein) complex deposits H3.3 into heterochromatin, where it is necessary for maintaining H3 Lys9 trimethylation and preventing transcription of silenced repetitive elements. H2A.Z is necessary for the maintenance of heterochromatin in animals, possibly because chaperones for canonical H2A are not active in heterochromatin outside of S phase. In plants, H2A.W, which wraps 162 bp of DNA, is necessary for heterochromatin condensation. Histone variants are typically incorporated into chromatin independently of DNA replication and modify chromatin properties. Recent studies have elucidated how particular histone variants are substrates of histone chaperones, chromatin remodellers and histone-modifying enzymes, thereby modifying DNA replication and repair, transcription and chromatin packaging. Most histones are assembled into nucleosomes behind the replication fork to package newly synthesized DNA. By contrast, histone variants, which are encoded by separate genes, are typically incorporated throughout the cell cycle. Histone variants can profoundly change chromatin properties, which in turn affect DNA replication and repair, transcription, and chromosome packaging and segregation. Recent advances in the study of histone replacement have elucidated the dynamic processes by which particular histone variants become substrates of histone chaperones, ATP-dependent chromatin remodellers and histone-modifying enzymes. Here, we review histone variant dynamics and the effects of replacing DNA synthesis-coupled histones with their replication-independent variants on the chromatin landscape.

The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl- into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl- channels in their basolateral membrane. Disrupting barttin/Cl- channel function impaired liquid absorption, and overexpressing barttin/Cl- channels increased absorption. Together, apical CFTR and basolateral barttin/Cl- channels provide an electrically conductive pathway for Cl- flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption.