A case study in the functional consequences of scaling the sizes of realistic cortical models.

Neuroscience models come in a wide range of scales and specificity, from mean-field rate models to large-scale networks of spiking neurons. There are potential trade-offs between simplicity and realism, versatility and computational speed. This paper is about large-scale cortical network models, and the question we address is one of scalability: would scaling down cell density impact a network's ability to reproduce cortical dynamics and function? We investigated this problem using a previously constructed realistic model of the monkey visual cortex that is true to size. Reducing cell density gradually up to 50-fold, we studied changes in model behavior. Size reduction without parameter adjustment was catastrophic. Surprisingly, relatively minor compensation in synaptic weights guided by a theoretical algorithm restored mean firing rates and basic function such as orientation selectivity to models 10-20 times smaller than the real cortex. Not all was normal in the reduced model cortices: intracellular dynamics acquired a character different from that of real neurons, and while the ability to relay feedforward inputs remained intact, reduced models showed signs of deficiency in functions that required dynamical interaction among cortical neurons. These findings are not confined to models of the visual cortex, and modelers should be aware of potential issues that accompany size reduction. Broader implications of this study include the importance of homeostatic maintenance of firing rates, and the functional consequences of feedforward versus recurrent dynamics, ideas that may shed light on other species and on systems suffering cell loss.

Task representations in neural networks trained to perform many cognitive tasks.

The brain has the ability to flexibly perform many tasks, but the underlying mechanism cannot be elucidated in traditional experimental and modeling studies designed for one task at a time. Here, we trained single network models to perform 20 cognitive tasks that depend on working memory, decision making, categorization, and inhibitory control. We found that after training, recurrent units can develop into clusters that are functionally specialized for different cognitive processes, and we introduce a simple yet effective measure to quantify relationships between single-unit neural representations of tasks. Learning often gives rise to compositionality of task representations, a critical feature for cognitive flexibility, whereby one task can be performed by recombining instructions for other tasks. Finally, networks developed mixed task selectivity similar to recorded prefrontal neurons after learning multiple tasks sequentially with a continual-learning technique. This work provides a computational platform to investigate neural representations of many cognitive tasks.

Inter-areal Balanced Amplification Enhances Signal Propagation in a Large-Scale Circuit Model of the Primate Cortex.

Understanding reliable signal transmission represents a notable challenge for cortical systems, which display a wide range of weights of feedforward and feedback connections among heterogeneous areas. We re-examine the question of signal transmission across the cortex in a network model based on mesoscopic directed and weighted inter-areal connectivity data of the macaque cortex. Our findings reveal that, in contrast to purely feedforward propagation models, the presence of long-range excitatory feedback projections could compromise stable signal propagation. Using population rate models as well as a spiking network model, we find that effective signal propagation can be accomplished by balanced amplification across cortical areas while ensuring dynamical stability. Moreover, the activation of prefrontal cortex in our model requires the input strength to exceed a threshold, which is consistent with the ignition model of conscious processing. These findings demonstrate our model as an anatomically realistic platform for investigations of global primate cortex dynamics.

Conserved Activity of Reassociated Homotetrameric Protein Subunits Released from Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles (MSN) with enlarged pores were prepared and characterized, and reversibly dissociated subunits of concanavalin A were entrapped in the mesopores, as shown by multiple biochemical and material characterizations. When loaded in the MSN, we demonstrated protein stability from proteases and, upon release, the subunits reassociated into active proteins shown through mannose binding and o-phthalaldehyde fluorescence. We have demonstrated a versatile and facile method to load homomeric proteins into MSN with potential applications in enhancing the delivery of large therapeutic proteins.

Organometallic Complexes Anchored to Conductive Carbon for Electrocatalytic Oxidation of Methane at Low Temperature.

Low-temperature direct methane fuel cells (DMEFCs) offer the opportunity to substantially improve the efficiency of energy production from natural gas. This study focuses on the development of well-defined platinum organometallic complexes covalently anchored to ordered mesoporous carbon (OMC) for electrochemical oxidation of methane in a proton exchange membrane fuel cell at 80 °C. A maximum normalized power of 403 µW/mg Pt was obtained, which was 5 times higher than the power obtained from a modern commercial catalyst and 2 orders of magnitude greater than that from a Pt black catalyst. The observed differences in catalytic activities for oxidation of methane are linked to the chemistry of the tethered catalysts, determined by X-ray photoelectron spectroscopy. The chemistry/activity relationships demonstrate a tangible path for the design of electrocatalytic systems for C-H bond activation that afford superior performance in DMEFC for potential commercial applications.

Geometry of the edge of chaos in a low-dimensional turbulent shear flow model.

We investigate the geometry of the edge of chaos for a nine-dimensional sinusoidal shear flow model and show how the shape of the edge of chaos changes with increasing Reynolds number. Furthermore, we numerically compute the scaling of the minimum perturbation required to drive the laminar attracting state into the turbulent region. We find this minimum perturbation to scale with the Reynolds number as Re(-2).

Caveolin-1 mediates inflammatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase.

With a propensity to invade the dermal lymphatic vessels of the skin overlying the breast and readily metastasize, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. We previously reported that caveolin-1 is overexpressed in IBC and that RhoC GTPase is a metastatic switch responsible for the invasive phenotype. RhoC-driven invasion requires phosphorylation by Akt1. Using a reliable IBC cell line we set out to determine if caveolin-1 expression affects RhoC-mediated IBC invasion. Caveolin-1 was down regulated by introduction of siRNA or a caveolin scaffolding domain. The ability of the cells to invade was tested and the status of Akt1 and RhoC GTPase examined. IBC cell invasion is significantly decreased when caveolin-1 is down regulated. Activation of Akt1 is decreased when caveolin-1 is down regulated, leading to decreased phosphorylation of RhoC GTPase. Thus, we report here that caveolin-1 overexpression mediates IBC cell invasion through activation Akt1, which phosphorylates RhoC GTPase.

Scaling of chaos versus periodicity: how certain is it that an attractor is chaotic?

The character of the time-asymptotic evolution of physical systems can have complex, singular behavior with variation of a system parameter, particularly when chaos is involved. A perturbation of the parameter by a small amount ε can convert an attractor from chaotic to nonchaotic or vice versa. We call a parameter value where this can happen ε uncertain. The probability that a random choice of the parameter is ε uncertain commonly scales like a power law in ε. Surprisingly, two seemingly similar ways of defining this scaling, both of physical interest, yield different numerical values for the scaling exponent. We show why this happens and present a quantitative analysis of this phenomenon.

Mimicking red blood cell lipid membrane to enhance the hemocompatibility of large-pore mesoporous silica.

Mesoporous silica nanoparticles (MSNs) have been repeatedly demonstrated as potential drug-delivery devices. The study of biocompatibility and interaction of these materials with the various cell types is of great interest with regard to the development of viable pharmaceutical products. By mimicking the cholesterol, phosphatidylcholine, and phosphatidylethanolamine composition of the outer leaflet of a human red blood cell (RBC), lipid-bilayer-coated mesoporous silica particles show considerably improved hemocompatibility over phosphatidylcholine-coated and uncoated large-pore MSN (l-MSN). These inorganic/organic composite nanomaterials are shown to be capable of interfacing with RBCs without damaging the cells even at relatively high concentrations, as observed through electron microscopy, UV-vis spectroscopy, and flow cytometry analyses. Interestingly, the absence of cholesterol in the outer bilayer composition is shown to produce toxic effects without resulting in hemolysis. By maintaining the ζ potential of lipid-bilayer-functionalized MSNs similar to that of the hemolytic l-MSNs, we demonstrate that the bilayer composition, and not the surface charge, plays a significant role in determining the hemocompatibility of MSN-based materials.

1,25 Dihydroxyvitamin D3 uptake is localized at caveolae and requires caveolar function.

Vitamin D3 is an essential vitamin that has been extensively studied due to its potential role as therapeutic for many diseases, including breast cancer. Previous research has indicated that calcitriol, the active form of Vitamin D3 has a negative effect on the metastatic ability of Inflammatory Breast Cancer (IBC) cells however the mechanism is not fully understood. The effect of calcitriol on IBC cells starting from cellular uptake must be investigated in order to understand these therapeutic effects. Calcitriol bound Quantum Dots (CalQDs) are a novel nanoparticle conjugated probe that can be used to directly examine the distribution, uptake, and signaling of calcitriol in live cells. Therefore we used these conjugated probes to directly investigate the uptake of calcitriol into live IBC cells. Interestingly, calcitriol uptake was observed to decrease when caveolae mediated endocytosis is disrupted. A luciferase assay confirmed that caveolae function is necessary; since calcitriol mediated activity decreases when caveolae mediated endocytosis is disrupted in IBC cells. In vitro examination of the localization of the probe indicated colocalization between caveolae and CalQDs. Additionally, Vitamin D Receptor (VDR) colocalization was observed with caveolae and calcitriol. This study demonstrates that in IBC cells calcitriol enters cells via caveolae mediated endocytosis and that caveolae are required for calcitriol to be uptaken at the increased rate.

Polymer-based stimuli-responsive nanosystems for biomedical applications.

The application of organic polymers and inorganic/organic hybrid systems in numerous fields of biotechnology has seen a considerable growth in recent years. Typically, organic polymers with diverse structures, compositional variations and differing molecular weights have been utilized to assemble polymeric nanosystems such as polymeric micelles, polymersomes, and nanohydrogels with unique features and structural properties. The architecture of these polymeric nanosystems involves the use of both hydrophobic and hydrophilic polymeric blocks, making them suitable as vehicles for diagnostic and therapeutic applications. Recently, "smart" or "intelligent" polymers have attracted significant attention in the biomedical field wherein careful introduction of specific polymeric modalities changes a banal polymeric nanosystem to an advanced stimuli-responsive nanosystem capable of performing extraordinary functions in response to an internal or external trigger such as pH, temperature, redox, enzymes, light, magnetic, or ultrasound. Further, incorporation of inorganic nanoparticles such as gold, silica, or iron oxide with surface-bound stimuli-responsive polymers offers additional advantages and multifunctionality in the field of nanomedicine. This review covers the physical properties and applications of both organic and organic/inorganic hybrid nanosystems with specific recent breakthroughs in drug delivery, imaging, tissue engineering, and separations and provides a brief discussion on the future direction.

Bactericidal/permeability increasing protein: a multifaceted protein with functions beyond LPS neutralization.

Bactericidal permeability increasing protein (BPI), a 55-60 kDa protein, first reported in 1975, has gone a long way as a protein with multifunctional roles. Its classical role in neutralizing endotoxin (LPS) raised high hopes among septic shock patients. Today, BPI is not just a LPS-neutralizing protein, but a protein with diverse functions. These functions can be as varied as inhibition of endothelial cell growth and inhibition of dendritic cell maturation, or as an anti-angiogenic, chemoattractant or opsonization agent. Though the literature available is extremely limited, it is fascinating to look into how BPI is gaining major importance as a signalling molecule. In this review, we briefly summarize the recent research focused on the multiple roles of BPI and its use as a therapeutic.

Differential effects of vitamin D treatment on inflammatory and non-inflammatory breast cancer cell lines.

Vitamin D is a known regulator of breast cancer cell proliferation, apoptosis, migration, invasion and differentiation in vitro. Recent studies have suggested a preventative role for vitamin D in breast cancer development and suggested a possible therapeutic application of vitamin D for patients with various forms of breast cancer. Inflammatory breast cancer (IBC) is a highly aggressive and phenotypically unique form of breast cancer that has a very poor prognosis. IBC invades the dermal lymphatics of the breast as tumor emboli early in the course of the disease. Because of the invasive nature of IBC, novel therapeutics are needed desperately. In the current study we examined the effect of the active form of vitamin D, calcitriol, treatment on the aggressive IBC phenotype. Herein we demonstrate that although the vitamin D receptor (VDR) is present in both IBC and non-IBC cell lines, the effect of vitamin D treatment is significant only on the IBC cells. SUM149 IBC cells showed increased protein concentration in response to 24 h of calcitriol exposure; likely mediated by an increase in protein synthesis as opposed to increased cellular proliferation. In addition, treatment with 100 nM calcitriol showed a significant decrease in SUM149 migration (67.8 % decrease, P = 0.030), invasion (43.9 % decrease, P = 0.015), and tumor spheroid size (69.4 % decrease, P = 0.018) compared to nontreated control groups. Finally, calcitriol treatment of SUM149 cells led to significantly fewer IBC experimental metastases as compared to control. Our study demonstrates that calcitriol treatment of SUM149 affected several of the processes important for IBC metastasis but had little effect on MDA-MB-231 cells. Therefore, calcitriol treatment may have the potential to decrease the rate and incidence of metastasis in IBC patients.