Modeling Maintenance of Long-Term Potentiation in Clustered Synapses, Long-Term Memory Without Bistability

Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses. However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Bistability of single synapses has also never been empirically demonstrated. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence. Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (in excess of 1 yr) persistence of groups of strong synapses. A unimodal weight distribution results. For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years. These simulations concur with recent data to support the clustered plasticity hypothesis, which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions, and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory.Comment: 17 pages, 5 figure

Auxin regulates SCFTIR1-dependent degradation of AUX/IAA proteins

The plant hormone auxin is central in many aspects of plant development. Previous studies have implicated the ubiquitin-ligase SCFTIR1 and the AUX/IAA proteins in auxin response. Dominant mutations in several AUX/IAA genes confer pleiotropic auxin-related phenotypes, whereas recessive mutations affecting the function of SCFTIR1 decrease auxin response. Here we show that SCFTIR1 is required for AUX/IAA degradation. We demonstrate that SCFTIR1 interacts with AXR2/IAA7 and AXR3/IAA17, and that domain II of these proteins is necessary and sufficient for this interaction. Further, auxin stimulates binding of SCFTIR1 to the AUX/IAA proteins, and their degradation. Because domain II is conserved in nearly all AUX/IAA proteins in Arabidopsis, we propose that auxin promotes the degradation of this large family of transcriptional regulators, leading to diverse downstream effects

A new level-dependent coarsegrid correction scheme for indefinite Helmholtz problems

In this paper we construct and analyse a level-dependent coarsegrid correction scheme for indefinite Helmholtz problems. This adapted multigrid method is capable of solving the Helmholtz equation on the finest grid using a series of multigrid cycles with a grid-dependent complex shift, leading to a stable correction scheme on all levels. It is rigourously shown that the adaptation of the complex shift throughout the multigrid cycle maintains the functionality of the two-grid correction scheme, as no smooth modes are amplified in or added to the error. In addition, a sufficiently smoothing relaxation scheme should be applied to ensure damping of the oscillatory error components. Numerical experiments on various benchmark problems show the method to be competitive with or even outperform the current state-of-the-art multigrid-preconditioned Krylov methods, like e.g. CSL-preconditioned GMRES or BiCGStab.Comment: 21 page

Using a damper amplification factor to increase energy dissipation in structures

AbstractFluid dampers are an important tool for dissipating unwanted vibrations in a range of engineering structures. This paper examines the effects of amplifying the displacements transferred to a non-linear damper, to increase the effectiveness of the damper in a range of situations commonly encountered in civil engineering structures. These include, (i) the ability to “fine tune” the required damping for a particular size damper, (ii) the ability to have a set of the same size dampers, but with different amplification factors to achieve a specific damping task, and (iii) to increase the sensitivity of the damper to small movements which effectively extends the range over which the damper works. Through numerical simulations and experimental tests conducted on a non-linear damper, we quantify the potential advantages of adding an amplification factor and the range of parameters where the benefit to this device is significant. The example of a two-storey structure is used as a test case and real-time dynamic substructuring tests are used to assess the complete system performance using a range of different amplification factors. The results show that the structural performance is most improved for frequencies close to resonance and that the amplification factor has an effective limit that for the case considered in this study is of approximately 3. The effects of the mechanism compliance are also assessed

A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis.

Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative-feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature

The malleable brain: plasticity of neural circuits and behavior: A review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation (LTP) and long-term depression (LTD) respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by LTP and LTD, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.Fil: Schaefer, Natascha. University of Wuerzburg; AlemaniaFil: Rotermund, Carola. University of Tuebingen; AlemaniaFil: Blumrich, Eva Maria. Universitat Bremen; AlemaniaFil: Lourenco, Mychael V.. Universidade Federal do Rio de Janeiro; BrasilFil: Joshi, Pooja. Robert Debre Hospital; FranciaFil: Hegemann, Regina U.. University of Otago; Nueva ZelandaFil: Jamwal, Sumit. ISF College of Pharmacy; IndiaFil: Ali, Nilufar. Augusta University; Estados UnidosFil: García Romero, Ezra Michelet. Universidad Veracruzana; MéxicoFil: Sharma, Sorabh. Birla Institute of Technology and Science; IndiaFil: Ghosh, Shampa. Indian Council of Medical Research; IndiaFil: Sinha, Jitendra K.. Indian Council of Medical Research; IndiaFil: Loke, Hannah. Hudson Institute of Medical Research; AustraliaFil: Jain, Vishal. Defence Institute of Physiology and Allied Sciences; IndiaFil: Lepeta, Katarzyna. Polish Academy of Sciences; ArgentinaFil: Salamian, Ahmad. Polish Academy of Sciences; ArgentinaFil: Sharma, Mahima. Polish Academy of Sciences; ArgentinaFil: Golpich, Mojtaba. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Nawrotek, Katarzyna. University Of Lodz; ArgentinaFil: Paid, Ramesh K.. Indian Institute of Chemical Biology; IndiaFil: Shahidzadeh, Sheila M.. Syracuse University; Estados UnidosFil: Piermartiri, Tetsade. Universidade Federal de Santa Catarina; BrasilFil: Amini, Elham. University Kebangsaan Malaysia Medical Centre; MalasiaFil: Pastor, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Wilson, Yvette. University of Melbourne; AustraliaFil: Adeniyi, Philip A.. Afe Babalola University; NigeriaFil: Datusalia, Ashok K.. National Brain Research Centre; IndiaFil: Vafadari, Benham. Polish Academy of Sciences; ArgentinaFil: Saini, Vedangana. University of Nebraska; Estados UnidosFil: Suárez Pozos, Edna. Instituto Politécnico Nacional; MéxicoFil: Kushwah, Neetu. Defence Institute of Physiology and Allied Sciences; IndiaFil: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Turner, Anthony J.. University of Leeds; Reino Unid

Quantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells

Cells are constantly exposed to Reactive Oxygen Species (ROS) produced both endogenously to meet physiological requirements and from exogenous sources. While endogenous ROS are considered as important signalling molecules, high uncontrollable ROS are detrimental. It is unclear how cells can achieve a balance between maintaining physiological redox homeostasis and robustly activate the antioxidant system to remove exogenous ROS. We have utilised a Systems Biology approach to understand how this robust adaptive system fulfils homeostatic requirements of maintaining steady-state ROS and growth rate, while undergoing rapid readjustment under challenged conditions. Using a panel of human ovarian and normal cell lines, we experimentally quantified and established interrelationships between key elements of ROS homeostasis. The basal levels of NRF2 and KEAP1 were cell line specific and maintained in tight correlation with their growth rates and ROS. Furthermore, perturbation of this balance triggered cell specific kinetics of NRF2 nuclear–cytoplasmic relocalisation and sequestration of exogenous ROS. Our experimental data were employed to parameterise a mathematical model of the NRF2 pathway that elucidated key response mechanisms of redox regulation and showed that the dynamics of NRF2-H2O2 regulation defines a relationship between half-life, total and nuclear NRF2 level and endogenous H2O2 that is cell line specific

Identification of stable endogenous reference genes for real-time PCR in the human fetal gonad using an external standard technique

Peer reviewedPostprin

Stiffness pathologies in discrete granular systems: bifurcation, neutral equilibrium, and instability in the presence of kinematic constraints

The paper develops the stiffness relationship between the movements and forces among a system of discrete interacting grains. The approach is similar to that used in structural analysis, but the stiffness matrix of granular material is inherently non-symmetric because of the geometrics of particle interactions and of the frictional behavior of the contacts. Internal geometric constraints are imposed by the particles' shapes, in particular, by the surface curvatures of the particles at their points of contact. Moreover, the stiffness relationship is incrementally non-linear, and even small assemblies require the analysis of multiple stiffness branches, with each branch region being a pointed convex cone in displacement-space. These aspects of the particle-level stiffness relationship gives rise to three types of micro-scale failure: neutral equilibrium, bifurcation and path instability, and instability of equilibrium. These three pathologies are defined in the context of four types of displacement constraints, which can be readily analyzed with certain generalized inverses. That is, instability and non-uniqueness are investigated in the presence of kinematic constraints. Bifurcation paths can be either stable or unstable, as determined with the Hill-Bazant-Petryk criterion. Examples of simple granular systems of three, sixteen, and sixty four disks are analyzed. With each system, multiple contacts were assumed to be at the friction limit. Even with these small systems, micro-scale failure is expressed in many different forms, with some systems having hundreds of micro-scale failure modes. The examples suggest that micro-scale failure is pervasive within granular materials, with particle arrangements being in a nearly continual state of instability