1,786 research outputs found

    Modeling genetic epilepsies in a dish

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    Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, provide a powerful platform for mechanistic studies of disorders of neurodevelopment and neural networks. hPSC models of autism, epilepsy, and other neurological disorders are also advancing the path toward designing and testing precision therapies. The field is evolving rapidly with the addition of genome‐editing approaches, expanding protocols for the two‐dimensional (2D) differentiation of different neuronal subtypes, and three‐dimensional (3D) human brain organoid cultures. However, the application of these techniques to study complex neurological disorders, including the epilepsies, remains a challenge. Here, we review previous work using both 2D and 3D hPSC models of genetic epilepsies, as well as recent advances in the field. We also describe new strategies for applying these technologies to disease modeling of genetic epilepsies, and discuss current challenges and future directions.Key FindingsZebrafish post‐embryonic intestinal development is slow during the first two weeks due to proliferation pattern.Transformation to the juvenile intestine is preceded by increased proliferation and changes in mitotic pattern.cells integrate between proliferating fold base epithelial cells and may regulate proliferation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153080/1/dvdy79.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153080/2/dvdy79_am.pd

    The effect of surface flooding on the physical-biogeochemical dynamics of a warm-core eddy off southeast Australia

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    Warm-core eddies (WCEs) formed from the East Australian Current (EAC) play an important role in the heat, mass and biogeochemical budgets of the western Tasman Sea. The development and separation of an EAC WCE during July-December 2008 was observed using remotely sensed temperature, ocean colour and sea-level elevation, three Argo floats, a shipboard CTD, a shelf mooring array and a 15-day deployment of a Slocum glider. The eddy formed from an EAC meander during the first half of 2008 and in late August had a ~275m deep surface mixed layer. In the two months before separation in early December, fresher and warmer EAC water flooded the top of the eddy, submerging the winter mixed layer. The rate of vertical transport due to submergence was estimated to be between 1 and 6Sv, at the time accounting for a significant fraction of the mean southward flow of the EAC. The core of the eddy had a surface chlorophyll a concentration of <0.4mgm-3 throughout the observations. A 20-40m thick pycnocline formed at the interface of the flooding surface waters and the submerged layer. Chlorophyll a concentration in the pycnocline ranged from 0.5 to 2mgm-3, with depth-integrated concentration ranging between 25 and 75mgm-2. The development of a sub-surface maximum suggests that flooding increased light levels in the pycnocline. Elevated levels of coloured dissolved organic matter in the submerged layer correspond to oxygen depletion, suggesting respiration of organic matter. A comparison is made with observations from WCEs in 1978 and 1997 in which, unusually, surface flooding did not occur, but solar heating stratified the top 50m. In the two eddies with surface capping, surface chlorophyll a concentrations were an order of magnitude higher than the 2008 flooded eddy, but depth-integrated chlorophyll a was similar. These findings suggest that EAC WCEs with relatively shallow surface flooding contain more phytoplankton biomass than surface images would suggest, with the vertical position of the chlorophyll a maximum depending on whether, and to what depth, the winter surface mixed layer is submerged. © 2010 Elsevier Ltd

    Successful new product development by optimizing development process effectiveness in highly regulated sectors: the case of the Spanish medical devices sector

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    Rapid development and commercialization of new products is of vital importance for small and medium sized enterprises (SME) in regulated sectors. Due to strict regulations, competitive advantage can hardly be achieved through the effectiveness of product concepts only. If an SME in a highly regulated sector wants to excell in new product development (NPD) performance, the company should focus on the flexibility, speed, and productivity of its NPD function: i.e. the development process effectiveness. Our main research goals are first to explore if SMEs should focus on their their development process effectiveness rather than on their product concept effectiveness to achieve high NPD performance; and second, to explore whether a shared pattern in the organization of the NPD function can be recognized to affect NPD performance positively. The medical devices sector in Spain is used as an example of a\ud highly regulated sector. A structured survey among 11 SMEs, of which 2 were studied also as in in-depth case studies, led to the following results. First of all, indeed the companies in the dataset which focused on the effectiveness of their development process, stood out in NPD performance. Further, the higher performing companies did have a number of commonalities in the organisation of their NPD function: 1) The majority of the higher performing firms had an NPD strategy characterized by a predominantly incremental project portfolio.\ud 2) a) Successful firms with an incremental project portfolio combined this with a functional team structure b) Successful firms with a radical project portfolio combined this with a heavyweight or autonomous team structure.\ud 3) A negative reciprocal relationship exists between formalization of the NPD processes and the climate of the NPD function, in that a formalized NPD process and an innovative climate do not seem to reinforce each other. Innovative climate combined with an informal NPD process does however contribute positively to NPD performance. This effect was stronger in combination with a radical project portfolio. The highest NPD performance was measured for companies focusing mainly on incremental innovation. It is argued that in highly regulated sectors, companies with an incremental product portfolio would benefit from employing a functional structure. Those companies who choose for a more radical project portfolio in highly regulated sectors should be aware\ud that they are likely to excell only in the longer term by focusing on strategic flexibility. In their NPD organization, they might be well advised to combine informal innovation processes with an innovative climate

    Risk-Driven Design Processes: Balancing Efficiency with Resilience in Product Design

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    Current design methods and approaches focus on increasing the efficiency of the product design system by, for example, eliminating waste and focusing on value creation. However, continuing failures in the development of complex, large scale products and systems point towards weaknesses in the existing approaches. We argue that product development organizations are hindered by the many uncertainties that are inherent in the process. Common management heuristics ignore uncertainty and thus overly simplify the decision making process. Creating transparency regarding uncertainties and the associated risks (i.e. effect of uncertainties on design objectives) is not seen as an explicit priority. Consequently organizations are unable to balance risk and return in their development choices. Product development processes do not emphasize reduction of risks, particularly those risks that are apparent early in the process. In addition, the resilience of the PD system, i.e. its ability to deliver on-target results under uncertainty, is not deliberately designed to match the level of residual uncertainty. This chapter introduces the notion of Risk-Driven Design and its four principles of 1. Creating transparency regarding design risks; 2. Risk-driven decision making; 3. Minimizing uncertainty; and 4. Creating resilience.Massachusetts Institute of Technology. Lean Advancement InitiativeCenter for Clean Water and Clean Energy at MIT and KFUP

    The World Hip Trauma Evaluation Study 3 HEMIARTHROPLASTY EVALUATION BY MULTICENTRE INVESTIGATION - WHiTE 3: HEMI - AN ABRIDGED PROTOCOL

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    Approximately half of all hip fractures are displaced intracapsular fractures. The standard treatment for these fractures is either hemiarthroplasty or total hip arthroplasty. The recent National Institute for Health and Care Excellence (NICE) guidance on hip fracture management recommends the use of 'proven' cemented stem arthroplasty with an Orthopaedic Device Evaluation Panel (ODEP) rating of at least 3B (97% survival at three years). The Thompsons prosthesis is currently lacking an ODEP rating despite over 50 years of clinical use, likely due to the paucity of implant survival data. Nationally, adherence to these guidelines is varied as there is debate as to which prosthesis optimises patient outcomes.This study design is a multi-centre, multi-surgeon, parallel, two arm, standard-of-care pragmatic randomised controlled trial. It will be embedded within the WHiTE Comprehensive Cohort Study (ISRCTN63982700). The main analysis is a two-way equivalence comparison between Hemi-Thompson and Hemi-Exeter polished taper with Unitrax head. Secondary outcomes will include radiological leg length discrepancy measured as per Bidwai and Willett, mortality, re-operation rate and indication for re-operation, length of index hospital stay and revision at four months. This study will be supplemented by the NHFD (National Hip Fracture Database) dataset.Evidence on the optimum choice of prosthesis for hemiarthroplasty of the hip is lacking. National guidance is currently based on expert opinion rather than empirical evidence. The incidence of hip fracture is likely to continue to increase and providing high quality evidence on the optimumCite this article: A. L. Sims. The World Hip Trauma Evaluation Study 3: Hemiarthroplasty Evaluation by Multicentre Investigation - WHITE 3: HEMI - An Abridged Protocol. Bone Joint Res 2016;5:18-25. doi: 10.1302/2046-3758.51.2000473

    Intracellular Proton Conductance of the Hepatitis C Virus p7 Protein and Its Contribution to Infectious Virus Production

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    The hepatitis C virus (HCV) p7 protein is critical for virus production and an attractive antiviral target. p7 is an ion channel when reconstituted in artificial lipid bilayers, but channel function has not been demonstrated in vivo and it is unknown whether p7 channel activity plays a critical role in virus production. To evaluate the contribution of p7 to organelle pH regulation and virus production, we incorporated a fluorescent pH sensor within native, intracellular vesicles in the presence or absence of p7 expression. p7 increased proton (H+) conductance in vesicles and was able to rapidly equilibrate H+ gradients. This conductance was blocked by the viroporin inhibitors amantadine, rimantadine and hexamethylene amiloride. Fluorescence microscopy using pH indicators in live cells showed that both HCV infection and expression of p7 from replicon RNAs reduced the number of highly acidic (pH<5) vesicles and increased lysosomal pH from 4.5 to 6.0. These effects were not present in uninfected cells, sub-genomic replicon cells not expressing p7, or cells electroporated with viral RNA containing a channel-inactive p7 point mutation. The acidification inhibitor, bafilomycin A1, partially restored virus production to cells electroporated with viral RNA containing the channel inactive mutation, yet did not in cells containing p7-deleted RNA. Expression of influenza M2 protein also complemented the p7 mutant, confirming a requirement for H+ channel activity in virus production. Accordingly, exposure to acid pH rendered intracellular HCV particles non-infectious, whereas the infectivity of extracellular virions was acid stable and unaffected by incubation at low pH, further demonstrating a key requirement for p7-induced loss of acidification. We conclude that p7 functions as a H+ permeation pathway, acting to prevent acidification in otherwise acidic intracellular compartments. This loss of acidification is required for productive HCV infection, possibly through protecting nascent virus particles during an as yet uncharacterized maturation process

    Impact of Community-Based Larviciding on the Prevalence of Malaria Infection in Dar es Salaam, Tanzania.

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    The use of larval source management is not prioritized by contemporary malaria control programs in sub-Saharan Africa despite historical success. Larviciding, in particular, could be effective in urban areas where transmission is focal and accessibility to Anopheles breeding habitats is generally easier than in rural settings. The objective of this study is to assess the effectiveness of a community-based microbial larviciding intervention to reduce the prevalence of malaria infection in Dar es Salaam, United Republic of Tanzania. Larviciding was implemented in 3 out of 15 targeted wards of Dar es Salaam in 2006 after two years of baseline data collection. This intervention was subsequently scaled up to 9 wards a year later, and to all 15 targeted wards in 2008. Continuous randomized cluster sampling of malaria prevalence and socio-demographic characteristics was carried out during 6 survey rounds (2004-2008), which included both cross-sectional and longitudinal data (N = 64,537). Bayesian random effects logistic regression models were used to quantify the effect of the intervention on malaria prevalence at the individual level. Effect size estimates suggest a significant protective effect of the larviciding intervention. After adjustment for confounders, the odds of individuals living in areas treated with larviciding being infected with malaria were 21% lower (Odds Ratio = 0.79; 95% Credible Intervals: 0.66-0.93) than those who lived in areas not treated. The larviciding intervention was most effective during dry seasons and had synergistic effects with other protective measures such as use of insecticide-treated bed nets and house proofing (i.e., complete ceiling or window screens). A large-scale community-based larviciding intervention significantly reduced the prevalence of malaria infection in urban Dar es Salaam

    Evaluation of alternative mosquito sampling methods for malaria vectors in Lowland South - East Zambia.

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    Sampling malaria vectors and measuring their biting density is of paramount importance for entomological surveys of malaria transmission. Human landing catch (HLC) has been traditionally regarded as a gold standard method for surveying human exposure to mosquito bites. However, due to the risk of human participant exposure to mosquito-borne parasites and viruses, a variety of alternative, exposure-free trapping methods were compared in lowland, south-east Zambia. Centres for Disease Control and Prevention miniature light trap (CDC-LT), Ifakara Tent Trap model C (ITT-C), resting boxes (RB) and window exit traps (WET) were all compared with HLC using a 3 × 3 Latin Squares design replicated in 4 blocks of 3 houses with long lasting insecticidal nets, half of which were also sprayed with a residual deltamethrin formulation, which was repeated for 10 rounds of 3 nights of rotation each during both the dry and wet seasons. The mean catches of HLC indoor, HLC outdoor, CDC-LT, ITT-C, WET, RB indoor and RB outdoor, were 1.687, 1.004, 3.267, 0.088, 0.004, 0.000 and 0.008 for Anopheles quadriannulatus Theobald respectively, and 7.287, 6.784, 10.958, 5.875, 0.296, 0.158 and 0.458, for An. funestus Giles, respectively. Indoor CDC-LT was more efficient in sampling An. quadriannulatus and An. funestus than HLC indoor (Relative rate [95% Confidence Interval] = 1.873 [1.653, 2.122] and 1.532 [1.441, 1.628], respectively, P < 0.001 for both). ITT-C was the only other alternative which had comparable sensitivity (RR = 0.821 [0.765, 0.881], P < 0.001), relative to HLC indoor other than CDC-LT for sampling An. funestus. While the two most sensitive exposure-free techniques primarily capture host-seeking mosquitoes, both have substantial disadvantages for routine community-based surveillance applications: the CDC-LT requires regular recharging of batteries while the bulkiness of ITT-C makes it difficult to move between sampling locations. RB placed indoors or outdoors and WET had consistently poor sensitivity so it may be useful to evaluate additional alternative methods, such as pyrethrum spray catches and back packer aspirators, for catching resting mosquitoes
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