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"Brain, Ruth"
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بناء القدرات الدماغية : أحدث الطرق المبتكرة لحماية وتحديد القدرات الكامنة في الدماغ
ينظر جراح الأعصاب إلى الدماغ باعتباره أعظم آلة أو جهاز ظهر على سطح الأرض حتى الآن. ورغم أن هذا الجراح يقوم بدراسة الدماغ ومعالجته بصورة مستمرة كلما استطاع إلى ذلك سبيلا دهشته إزاء عظمة خلقه لا تخبو ولا تذوي أبدا. أما الكاتب العلمي فأنه يعتبر الدماغ ميدانا رائعا للبحث العلمي وعالما غامضا على الدوام، فرغم الاكتشافات التي يتم التوصل إليها بين حين وآخر، فإنه يظل هناك الكثير من الاسرار التي تحيط به ولابد من إماطة اللثام عنهما. لقد قمنا سويا باجراء الدراسات والبحوث والمقابلات لإعداد هذا الكتاب الذي يبحث في مواضيع وثيقة الصلة بعلم الأعصاب. ويعتبر ميدان هذا العلم من أسرع الميادين العلمية نموا وتطورا، إذ تتمخض جهود الباحثين فيه عن كميات هائلة من المعلومات الجديدة.
Book
Autoregulatory and paracrine control of synaptic and behavioral plasticity by octopaminergic signaling
Hunger makes
Drosophila
larvae move faster in search of food. Koon and colleagues show that starvation increases the branching of octopaminergic motoneurons' axonal terminal arbors, driven by octopamine released from these same motoneurons. The increased locomotor activity of starved larvae requires octopaminergic signaling.
Adrenergic signaling has important roles in synaptic plasticity and metaplasticity. However, the underlying mechanisms of these functions remain poorly understood. We investigated the role of octopamine, the invertebrate counterpart of adrenaline and noradrenaline, in synaptic and behavioral plasticity in
Drosophila
. We found that an increase in locomotor speed induced by food deprivation was accompanied by an activity- and octopamine-dependent extension of octopaminergic arbors and that the formation and maintenance of these arbors required electrical activity. Growth of octopaminergic arbors was controlled by a cAMP- and CREB-dependent positive-feedback mechanism that required Octβ2R octopamine autoreceptors. Notably, this autoregulation was necessary for the locomotor response. In addition, octopamine neurons regulated the expansion of excitatory glutamatergic neuromuscular arbors through Octβ2Rs on glutamatergic motor neurons. Our results provide a mechanism for global regulation of excitatory synapses, presumably to maintain synaptic and behavioral plasticity in a dynamic range.
Journal Article
A half-centre oscillator encodes sleep pressure
Oscillatory neural dynamics are an inseparable part of mammalian sleep. Characteristic rhythms are associated with different sleep stages and variable levels of sleep pressure, but it remains unclear whether these oscillations are passive mirrors or active generators of sleep. Here we report that sleep–control neurons innervating the dorsal fan–shaped body of Drosophila (dFBNs) produce slow–wave activity (SWA) in the delta frequency band (0.2–1 Hz) that is causally linked to sleep. The dFBN ensemble contains one or two rhythmic cells per hemisphere whose membrane voltages oscillate in anti–phase between hyperpolarized DOWN and depolarized UP states releasing bursts of action potentials. The oscillations rely on direct interhemispheric competition of two inhibitory half–centres connected by glutamatergic synapses. Interference with glutamate release from these synapses disrupts SWA and baseline as well as rebound sleep, while the optogenetic replay of SWA (with the help of an intersectional, dFBN–restricted driver) induces sleep. Rhythmic dFBNs generate SWA throughout the sleep–wake cycle—despite a mutually antagonistic ′flip-flop′ arrangement with arousing dopaminergic neurons—but adjust its power to sleep need via an interplay of sleep history–dependent increases in dFBN excitability and homeostatic depression of their efferent synapses, as we demonstrate transcriptionally, structurally, functionally, and with a simple computational model. The oscillatory format permits a durable encoding of sleep pressure over long time scales but requires downstream mechanisms that convert the amplitude–modulated periodic signal into binary sleep–wake states.Competing Interest StatementThe authors have declared no competing interest.
Paper
Process Integration of Interconnects
This chapter aims to introduce the reader to the challenges of on‐die interconnect integration as the semiconductor industry continues to march down the scaling path, with leading companies exercising high‐volume production at 45 nm and lower nodes as of 2010. Before we dive into the state‐of‐the‐art technology nodes, a brief review of the progression of complexity and incorporation of novel materials into the on‐die interconnect architecture during the last twenty years should prove beneficial.
Book Chapter
Capillary-driven reflow of thin copper films with submicron, high aspect ratio features
Conventional sputtering techniques are no longer sufficient for the fabrication of interconnects as trench widths enter the submicron regime and aspect ratios become greater than 1:1. The goal of this thesis is to investigate Cu as a potential interconnect metal for use in integrated circuit technology. Since sputtering is well established in the integrated circuit industry, we have used current sputtering technology as our deposition technique of choice. An alternative approach to modify the nonconformal deposition profiles obtained by sputtering is to reflow (planarize by capillary-driven surface diffusion) the metal film during a post-deposition anneal. In particular, reflow is performed for thin Cu films deposited on refractory metal barrier layers (Mo, Ta, and W) at temperatures $\\le$500$\\sp\\circ$C. With a goal of developing and understanding a post-deposition reflow process for Cu, we have studied the following topics. Chapter 1 introduces relevant current concepts in ultra-large scale integration for interconnect technology to motivate the approaches described in this thesis. Chapter 2 investigates several techniques to improve the initial Cu coverage obtained from a magnetron sputtering source. This was found to be necessary since thin Cu films agglomerate on many underlayers. Chapter 3 describes an investigation of the atomic transport mechanism during reflow of Cu films, to understand the kinetics of reflow and measure the appropriate kinetic constants. Extensive transmission electron microscope (TEM) work was done to examine reflowed profiles and to relate the extent of reflow to the microstructure of the Cu films. Hot-stage TEM experiments were performed to observe dynamically the reflow of a very low aspect ratio film. Chapter 4 develops a finite-element model to study surface diffusion mediated reflow in high aspect ratio trenches. We have considered (i) reflow of typical continuum, as-deposited profiles from a magnetron sputtering source, (ii) reflow of continuum profiles including an anisotropic surface energy and (iii) reflow with the inclusion of grain boundaries. We also discuss some limitations of a post-deposition reflow process, and we make recommendations to facilitate the ability to reflow Cu in high aspect ratio trenches. Finally, Chapter 5 examines a microwave annealing technique to reflow Cu films.
Dissertation
Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity
IgA
+
B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8
+
T cells.
The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA
+
) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8
+
T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8
+
T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA
+
cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8
+
T-lymphocyte activation as a tumour-promoting mechanism.
Increased cancer risk in fatty livers
Cancer progression beyond the early stages is thought to be caused in some cases by adaptive immunity, but its role remains controversial. In this study, Michael Karin and colleagues show that PD-L1-expressing IgA
+
B cells accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease. The inflammation-induced IgA
+
cells promote the progression to hepatocellular carcinoma by suppressing liver cytotoxic CD8
+
T cells that prevent the emergence of this aggressive tumour.
Journal Article
Maternal depression trajectories from pregnancy to 3 years postpartum are associated with children’s behavior and executive functions at 3 and 6 years
The objective of this study was to investigate how patterns of maternal depressive symptoms from mid-pregnancy to 3 years postpartum are associated with children’s behavior at age 3 years and executive functions. Maternal depressive symptoms were measured from mid-pregnancy to 3 years postpartum. Growth mixture modeling was used on standardized maternal depression scores (n = 147) to identify trajectories. Children’s behavioral problems and mental health symptomatology (internalizing, externalizing, and attention deficit hyperactivity disorder) were obtained at 3 and 6 years. EFs were assessed by a laboratory-based computerized task and maternal-report at 6 years. Multivariable linear regressions of children’s outcomes against maternal depressive symptom trajectories were conducted (n = 103). Three distinct patterns of maternal depressive symptom trajectories were identified: low (n = 105), increasing (n = 27), and decreasing (n = 15). Children of mothers whose depressive symptoms increased reported more problem behaviors at 3 years and poorer EFs at 6 years as assessed by both instruments, but no significant differences in mental health symptomatology at 6 years, relative to those whose mothers had consistently low depressive symptoms. Children whose mothers became less depressed over time had comparable levels of behavioral problems at age 3, executive functions, and internalizing and externalizing scores at age 6; and fewer reported ADHD behaviors at age 6, than those whose mothers remained less depressed over time. If mothers’ depressive symptoms improve over the first 3 years postpartum, their children’s outlook may be comparable to those whose mothers had consistently low depressive symptoms.
Journal Article
Seasonal variation in Guillain-Barré syndrome: a systematic review, meta-analysis and Oxfordshire cohort study
IntroductionEvidence for seasonal variation in incidence and subtype of Guillain-Barré syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis.MethodsWe searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001–2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype.ResultsAcross 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02–1.27, p=0.020), with significant heterogeneity between studies (I2=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18–3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84–5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60–2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75).DiscussionIncidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses.
Journal Article
Targeting proliferative retinopathy: Arginase 1 limits vitreoretinal neovascularization and promotes angiogenic repair
Current therapies for treatment of proliferative retinopathy focus on retinal neovascularization (RNV) during advanced disease and can trigger adverse side-effects. Here, we have tested a new strategy for limiting neurovascular injury and promoting repair during early-stage disease. We have recently shown that treatment with a stable, pegylated drug form of the ureohydrolase enzyme arginase 1 (A1) provides neuroprotection in acute models of ischemia/reperfusion injury, optic nerve crush, and ischemic stroke. Now, we have determined the effects of this treatment on RNV, vascular repair, and retinal function in the mouse oxygen-induced retinopathy (OIR) model of retinopathy of prematurity (ROP). Our studies in the OIR model show that treatment with pegylated A1 (PEG-A1), inhibits pathological RNV, promotes angiogenic repair, and improves retinal function by a mechanism involving decreased expression of TNF, iNOS, and VEGF and increased expression of FGF2 and A1. We further show that A1 is expressed in myeloid cells and areas of RNV in retinal sections from mice with OIR and human diabetic retinopathy (DR) patients and in blood samples from ROP patients. Moreover, studies using knockout mice with hemizygous deletion of A1 show worsened RNV and retinal injury, supporting the protective role of A1 in limiting the OIR-induced pathology. Collectively, A1 is critically involved in reparative angiogenesis and neuroprotection in OIR. Pegylated A1 may offer a novel therapy for limiting retinal injury and promoting repair during proliferative retinopathy.
Journal Article
Implementation of a nurse-delivered, community-based liver screening and assessment program for people with metabolic dysfunction-associated steatotic liver disease (LOCATE-NAFLD trial)
Background
With the high burden of Metabolic dysfunction-associated steatotic liver disease (MASLD), (previously known as Non-Alcoholic Fatty Liver Disease - NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of the LOCATE model.
Methods
The evaluation used mixed methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care.
Results
The LOCATE model was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk MASLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in MASLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support.
Conclusion
Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting.
Trial registration
The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) – ACTRN12620000158965.
Journal Article