Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain ...function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because schools materially influence both health and education, they substantially determine the future well-being and economic productivity of populations. Recent research suggests that healthier ...children learn better and that more educated adults are healthier. School health is a cross-disciplinary field of study and a fundamental strategy that can be used to improve both health and education outcomes. Modern school health programs include 10 interactive components: health education; physical education and physical activity; nutrition environment and services; health services; counseling, psychological, and social services; physical environment; social and emotional climate; family engagement; community involvement; and employee wellness. This review is written for both health and education audiences. It integrates recent research and developments in relationships among health, education, and economic outcomes; health and education systems; the school health program, its components, and their effectiveness; cross-disciplinary collaboration; local, state, national, and international infrastructures and strategies; implementation science; and relevant academic research, training, and service.
Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why ...the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.
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Children with autism have a significantly lower quality of life compared with their neurotypical peers. While multiple studies have quantified the impact of autism on health-related quality of life ...(HRQoL) through standardized surveys such as the PedsQL, none have specifically investigated the impact of
syndromic
autism. Here we evaluate HRQoL in children diagnosed with three genetic disorders that strongly predispose to syndromic autism: Phelan-McDermid syndrome (PMD), Rett syndrome (RTT), and
SYNGAP1
-related intellectual disability (
SYNGAP1
-ID). We find the most severely impacted dimension is physical functioning. Strikingly, syndromic autism results in worse quality of life than other chronic disorders including idiopathic autism. This study demonstrates the utility of caregiver surveys in prioritizing phenotypes, which may be targeted as clinical endpoints for genetically defined ASDs.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
ABSTRACT
BACKGROUND
As summarized in this article, the widespread implementation of modern school health education (SHE) could become one of the most effective means available to improve the ...well‐being of people in the United States and in other nations. However, the development and evolution of SHE largely remains unorganized, underdeveloped, and neglected by health and education agencies, policymakers, and the public.
METHODS
Essential to the development of any scientific discipline, scientists today use the word ontology to refer to efforts to organize knowledge in particular domains. A useful working definition of a scientific ontology is an explicit, formal specification of a shared conceptualization—a systematic set of shared terms and an explication of their interrelationships. Nine interdependent questions are outlined to help guide the development of an initial, broad, and actionable scientific ontology for SHE.
RESULTS
Whether and how we respond to these questions arguably will determine the future of SHE research, policy, practice, and equity in the United States.
CONCLUSIONS
An initial ontology might help conceptualize, inform, and facilitate more systematic and strategic local, state, national, and international deliberations and actions to improve SHE.
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Genome-scale models of metabolism and macromolecular expression (ME-models) explicitly compute the optimal proteome composition of a growing cell. ME-models expand upon the well-established ...genome-scale models of metabolism (M-models), and they enable a new fundamental understanding of cellular growth. ME-models have increased predictive capabilities and accuracy due to their inclusion of the biosynthetic costs for the machinery of life, but they come with a significant increase in model size and complexity. This challenge results in models which are both difficult to compute and challenging to understand conceptually. As a result, ME-models exist for only two organisms (Escherichia coli and Thermotoga maritima) and are still used by relatively few researchers. To address these challenges, we have developed a new software framework called COBRAme for building and simulating ME-models. It is coded in Python and built on COBRApy, a popular platform for using M-models. COBRAme streamlines computation and analysis of ME-models. It provides tools to simplify constructing and editing ME-models to enable ME-model reconstructions for new organisms. We used COBRAme to reconstruct a condensed E. coli ME-model called iJL1678b-ME. This reformulated model gives functionally identical solutions to previous E. coli ME-models while using 1/6 the number of free variables and solving in less than 10 minutes, a marked improvement over the 6 hour solve time of previous ME-model formulations. Errors in previous ME-models were also corrected leading to 52 additional genes that must be expressed in iJL1678b-ME to grow aerobically in glucose minimal in silico media. This manuscript outlines the architecture of COBRAme and demonstrates how ME-models can be created, modified, and shared most efficiently using the new software framework.
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While many studies have demonstrated positive associations between childhood obesity and adult metabolic risk, important questions remain as to the nature of the relationship. In particular, it is ...unclear whether the associations reflect the tracking of body mass index (BMI) from childhood to adulthood or an independent level of risk. This systematic review aimed to investigate the relationship between childhood obesity and a range of metabolic risk factors during adult life.
To perform an unbiased systematic review to investigate the association between childhood BMI and risk of developing components of metabolic disease in adulthood, and whether the associations observed are independent of adult BMI.
Electronic databases were searched from inception until July 2010 for studies investigating the association between childhood BMI and adult metabolic risk. Two investigators independently reviewed studies for eligibility according to the inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle-Ottawa Scale.
The search process identified 11 articles that fulfilled the inclusion and exclusion criteria. Although several identified weak positive associations between childhood BMI and adult total cholesterol, low-density lipo protein-cholesterol, triglyceride and insulin concentrations, these associations were ameliorated or inversed when adjusted for adult BMI or body fatness. Of the four papers that considered metabolic syndrome as an end point, none showed evidence of an independent association with childhood obesity.
Little evidence was found to support the view that childhood obesity is an independent risk factor for adult blood lipid status, insulin levels, metabolic syndrome or type 2 diabetes. The majority of studies failed to adjust for adult BMI and therefore the associations observed may reflect the tracking of BMI across the lifespan. Interestingly, where adult BMI was adjusted for, the data showed a weak negative association between childhood BMI and metabolic variables, with those at the lower end of the BMI range in childhood, but obese during adulthood at particular risk.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Antibody therapy of cancer Scott, Andrew M; Wolchok, Jedd D; Old, Lloyd J
Nature reviews. Cancer,
04/2012, Volume:
12, Issue:
4
Journal Article
Peer reviewed
The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid ...tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.
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