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861.
Alzbeta Trancikova Adamantios Mamais Philip J. Webber Klodjan Stafa Elpida Tsika Liliane Glauser Andrew B. West Rina Bandopadhyay Darren J. Moore 《PloS one》2012,7(10)
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of autosomal dominant familial Parkinson''s disease (PD). LRRK2 encodes a multi-domain protein containing GTPase and kinase enzymatic domains. Disease-associated mutations in LRRK2 variably influence enzymatic activity with the common G2019S variant leading to enhanced kinase activity. Mutant LRRK2 induces neuronal toxicity through a kinase-dependent mechanism suggesting that kinase activity is important for mediating the pathogenic effects of LRRK2 mutations. A number of LRRK2 kinase substrates have been identified in vitro but whether they represent authentic physiological substrates in mammalian cells or tissues is not yet clear. The eukaryotic initiation factor 4E (eIF4E)-binding protein, 4E-BP1, was recently identified as a potential substrate of LRRK2 kinase activity in vitro and in Drosophila with phosphorylation occurring at Thr37 and Thr46. Here, we explore a potential interaction of LRRK2 and 4E-BP1 in mammalian cells and brain. We find that LRRK2 can weakly phosphorylate 4E-BP1 in vitro but LRRK2 overexpression is not able to alter endogenous 4E-BP1 phosphorylation in mammalian cells. In mammalian neurons LRRK2 and 4E-BP1 display minimal co-localization, whereas the subcellular distribution, protein complex formation and covalent post-translational modification of endogenous 4E-BP1 are not altered in the brains of LRRK2 knockout or mutant LRRK2 transgenic mice. In the brain, the phosphorylation of 4E-BP1 at Thr37 and Thr46 does not change in LRRK2 knockout or mutant LRRK2 transgenic mice, nor is 4E-BP1 phosphorylation altered in idiopathic or G2019S mutant PD brains. Collectively, our results suggest that 4E-BP1 is neither a major nor robust physiological substrate of LRRK2 in mammalian cells or brain. 相似文献
862.
Victoria J. Wearmouth Matthew J. McHugh Nicolas E. Humphries Aurore Naegelen Mohammed Z. Ahmed Emily J. Southall Andrew M. Reynolds David W. Sims 《Proceedings. Biological sciences / The Royal Society》2014,281(1782)
The decisions animals make about how long to wait between activities can determine the success of diverse behaviours such as foraging, group formation or risk avoidance. Remarkably, for diverse animal species, including humans, spontaneous patterns of waiting times show random ‘burstiness’ that appears scale-invariant across a broad set of scales. However, a general theory linking this phenomenon across the animal kingdom currently lacks an ecological basis. Here, we demonstrate from tracking the activities of 15 sympatric predator species (cephalopods, sharks, skates and teleosts) under natural and controlled conditions that bursty waiting times are an intrinsic spontaneous behaviour well approximated by heavy-tailed (power-law) models over data ranges up to four orders of magnitude. Scaling exponents quantifying ratios of frequent short to rare very long waits are species-specific, being determined by traits such as foraging mode (active versus ambush predation), body size and prey preference. A stochastic–deterministic decision model reproduced the empirical waiting time scaling and species-specific exponents, indicating that apparently complex scaling can emerge from simple decisions. Results indicate temporal power-law scaling is a behavioural ‘rule of thumb’ that is tuned to species’ ecological traits, implying a common pattern may have naturally evolved that optimizes move–wait decisions in less predictable natural environments. 相似文献
863.
Nur Mohammad Monsur Hassan Nicole Painter C. Rolfe Howlett Andrew W. Farrell Nick Di Girolamo J. Guy Lyons Gary M. Halliday 《PloS one》2014,9(9)
Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm−/− mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm−/− mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm−/−, Trp53+/−, and particularly the Brm−/− Trp53+/− mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm−/− Trp53+/+ and Brm−/− Trp53+/− mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm−/− mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis. 相似文献
864.
John Faaborg Wayne J. Arendt Judith D. Toms Katie M. Dugger W. Andrew Cox Miguel Canals Mora 《Biodiversity and Conservation》2013,22(1):63-75
Despite concern expressed two decades ago, there has been little recent discussion about continuing declines of migrant bird populations. Monitoring efforts have been focused almost exclusively on the breeding grounds. We describe the long-term decline of a winter-resident bird population in Guánica Commonwealth Forest, Puerto Rico, one of the last remaining tracts of high-quality tropical dry forests in the Caribbean. The winter bird community has exhibited dramatic declines, with constant-effort mist netting now capturing about one-third as many birds as it did 20 years ago. Population estimates for the three most common species have declined dramatically, even though survival rates have remained constant, and other species are now virtually absent from a site where they once were fairly common. Although explanations for these declines are speculative, particularly because they involve multiple species, we argue that the strength and duration of these declines in well-preserved dry forest within a biosphere reserve should stimulate renewed discussion of migrant population trends and comparison with other recent monitoring activities. 相似文献
865.
866.
Christopher Williams Philip Wilson Jill Morrison Alex McMahon Walker Andrew Lesley Allan Alex McConnachie Yvonne McNeill Louise Tansey 《PloS one》2013,8(1)
Background
Access to Cognitive behavioural therapy (CBT) for depression is limited. One solution is CBT self-help books. Trial Objectives: To assess the impact of a guided self-help CBT book (GSH-CBT) on mood, compared to treatment as usual (TAU).Hypotheses:- GSH-CBT will have improved mood and knowledge of the causes and treatment of depression compared to the control receiving TAU
- Guided self-help will be acceptable to patients and staff.
Methods and Findings
Participants: Adults attending seven general practices in Glasgow, UK with a BDI-II score of ≥14. 141 randomised to GSH-CBT and 140 to TAU. Interventions: RCT comparing ‘Overcoming Depression: A Five Areas Approach’ book plus 3–4 short face to face support appointments totalling up to 2 hours of guided support, compared with general practitioner TAU. Primary outcome: The BDI (II) score at 4 months. Numbers analysed: 281 at baseline, 203 at 4 months (primary outcome), 117 at 12 months. Outcome: Mean BDI-II scores were lower in the GSH-CBT group at 4 months by 5.3 points (2.6 to 7.9, p<0.001). At 4 and 12 months there were also significantly higher proportions of participants achieving a 50% reduction in BDI-II in the GSH-CBT arm. The mean support was 2 sessions with 42.7 minutes for session 1, 41.4 minutes for session 2 and 40.2 minutes of support for session 3. Adverse effects/Harms: Significantly less deterioration in mood in GSH-CBT (2.0% compared to 9.8% in the TAU group for BDI—II category change).Limitations
Weaknesses: Our follow-up rate of 72.2% at 4 months is better than predicted but is poorer at 12 months (41.6%). In the GSH-CBT arm, around 50% of people attended 2 or fewer sessions. 22% failed to take up treatment.Conclusions
GSH-CBT is substantially more effective than TAU.Trial Registration
Controlled-Trials.com ISRCTN13475030 相似文献867.
Hang Xu Donald Bloswick Andrew Merryweather 《Computer methods in biomechanics and biomedical engineering》2013,16(11):1217-1224
Musculoskeletal models are widely used to investigate joint kinematics and predict muscle force during gait. However, the knee is usually simplified as a one degree of freedom joint and knee ligaments are neglected. The aim of this study was to develop an OpenSim gait model with enhanced knee structures. The knee joint in this study included three rotations and three translations. The three knee rotations and mediolateral translation were independent, with proximodistal and anteroposterior translations occurring as a function of knee flexion/extension. Ten elastic elements described the geometrical and mechanical properties of the anterior and posterior cruciate ligaments (ACL and PCL), and the medial and lateral collateral ligaments (MCL and LCL). The three independent knee rotations were evaluated using OpenSim to observe ligament function. The results showed that the anterior and posterior bundles of ACL and PCL (aACL, pACL and aPCL, pPCL) intersected during knee flexion. The aACL and pACL mainly provided force during knee flexion and adduction, respectively. The aPCL was slack throughout the range of three knee rotations; however, the pPCL was utilised for knee abduction and internal rotation. The LCL was employed for knee adduction and rotation, but was slack beyond 20° of knee flexion. The MCL bundles were mainly used during knee adduction and external rotation. All these results suggest that the functions of knee ligaments in this model approximated the behaviour of the physical knee and the enhanced knee structures can improve the ability to investigate knee joint biomechanics during various gait activities. 相似文献
868.
869.
Jonathan M. Behrendt David Nagel Evita Chundoo Lois M. Alexander Damien Dupin Anna V. Hine Mark Bradley Andrew J. Sutherland 《PloS one》2013,8(3)
The efficient transport of micron-sized beads into cells, via a non-endocytosis mediated mechanism, has only recently been described. As such there is considerable scope for optimization and exploitation of this procedure to enable imaging and sensing applications to be realized. Herein, we report the design, synthesis and characterization of fluorescent microsphere-based cellular delivery agents that can also carry biological cargoes. These core-shell polymer microspheres possess two distinct chemical environments; the core is hydrophobic and can be labeled with fluorescent dye, to permit visual tracking of the microsphere during and after cellular delivery, whilst the outer shell renders the external surfaces of the microspheres hydrophilic, thus facilitating both bioconjugation and cellular compatibility. Cross-linked core particles were prepared in a dispersion polymerization reaction employing styrene, divinylbenzene and a thiol-functionalized co-monomer. These core particles were then shelled in a seeded emulsion polymerization reaction, employing styrene, divinylbenzene and methacrylic acid, to generate orthogonally functionalized core-shell microspheres which were internally labeled via the core thiol moieties through reaction with a thiol reactive dye (DY630-maleimide). Following internal labeling, bioconjugation of green fluorescent protein (GFP) to their carboxyl-functionalized surfaces was successfully accomplished using standard coupling protocols. The resultant dual-labeled microspheres were visualized by both of the fully resolvable fluorescence emissions of their cores (DY630) and shells (GFP). In vitro cellular uptake of these microspheres by HeLa cells was demonstrated conventionally by fluorescence-based flow cytometry, whilst MTT assays demonstrated that 92% of HeLa cells remained viable after uptake. Due to their size and surface functionalities, these far-red-labeled microspheres are ideal candidates for in vitro, cellular delivery of proteins. 相似文献
870.
Oreenaiza Nordin Wesley Donald Wong Hong Ming Teoh Guat Ney Khairul Asuad Mohamed Nor Azlina Abdul Halim Peter Winskill Azahari Abdul Hadi Zulkamal Safi'in Muhammad Renaud Lacroix Sarah Scaife Andrew Robert McKemey Camilla Beech Murad Shahnaz Luke Alphey Derric David Nimmo Wasi Ahmed Nazni Han Lim Lee 《PloS one》2013,8(3)
Dengue is the most important mosquito-borne viral disease. No specific treatment or vaccine is currently available; traditional vector control methods can rarely achieve adequate control. Recently, the RIDL (Release of Insect carrying Dominant Lethality) approach has been developed, based on the sterile insect technique, in which genetically engineered ‘sterile’ homozygous RIDL male insects are released to mate wild females; the offspring inherit a copy of the RIDL construct and die. A RIDL strain of the dengue mosquito, Aedes aegypti, OX513A, expresses a fluorescent marker gene for identification (DsRed2) and a protein (tTAV) that causes the offspring to die. We examined whether these proteins could adversely affect predators that may feed on the insect. Aedes aegypti is a peri-domestic mosquito that typically breeds in small, rain-water-filled containers and has no specific predators. Toxorhynchites larvae feed on small aquatic organisms and are easily reared in the laboratory where they can be fed exclusively on mosquito larvae. To evaluate the effect of a predator feeding on a diet of RIDL insects, OX513A Ae. aegypti larvae were fed to two different species of Toxorhynchites (Tx. splendens and Tx. amboinensis) and effects on life table parameters of all life stages were compared to being fed on wild type larvae. No significant negative effect was observed on any life table parameter studied; this outcome and the benign nature of the expressed proteins (tTAV and DsRed2) indicate that Ae. aegypti OX513A RIDL strain is unlikely to have any adverse effects on predators in the environment. 相似文献