Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal ...dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.
► Microglia engulf presynaptic inputs undergoing active synaptic pruning ► Engulfment of developing synaptic inputs is dependent upon neural activity ► CR3/C3 signaling is necessary for microglia-mediated engulfment of synapses ► CR3/C3 signaling in microglia is required for proper synaptic connectivity
Schafer et al. demonstrate that microglia engulf presynaptic inputs in the postnatal brain in a manner dependent upon activity and the complement cascade. Furthermore, disrupting complement signaling in microglia results in sustained deficits in neuronal wiring.
The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent ...plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response.
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•Inducible gene programs are adapted to reflect the function of a neuron in a circuit•Neuronal activity induces a distinct transcriptional response in inhibitory neurons•Npas4 promotes development of excitatory synapses on SST-positive inhibitory neurons•Npas4 activates a set of inducible genes in SST neurons that function at synapses
Activity induces the same set of early transcription factors in inhibitory neurons as it does in excitatory ones, but the downstream targets in each cell type differ in a manner that likely preserves an excitatory-inhibitory balance in cortical circuits.
The influence of substrate topography and interfacial polymerization (IP) conditions were investigated during the fabrication of patterned thin-film composite (TFC) membranes. Aromatic and ...semi-aromatic polyamide layers were formed atop patterned ultrafiltration (UF) membrane supports by IP using different concentrations of m-phenylenediamine (MPD) or piperazine (PIP) in water of 0.01–2% w/v with a fixed concentration of trimesoyl chloride in hexane of 0.1% w/v. For all the conditions evaluated, TFC membranes with regular surface patterns were achieved by maintaining amine soaking time and IP reaction time within 120s. Importantly, the surface topography of the patterned TFC membranes was determined to be independent of IP reaction time. Characterization of the morphological details suggests non-conformal growth of the barrier layer on the patterned UF substrates. Results indicate that the extent of such non-conformal growth can be reduced by decreasing the amine concentration as well as by choosing an amine monomer such as PIP that produces a thinner semi-aromatic barrier layer. The overall findings of this study provide a means for achieving desired surface features for specific membrane applications.
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•TFC membranes were synthesized by interfacial polymerization (IP) on nanoimprinted ultrafiltration (UF) membrane supports.•The effects of UF support as well as chemistry and processing time of IP were examined.•The barrier layer growth appeared to be non-conformal, and was tunable with the IP chemistry and process conditions.•The patterned TFC membranes have performances between typical RO and NF TFC membranes.
Neuronal development is characterized by a period of exuberant synaptic growth that is well studied. However, the mechanisms that restrict this process are less clear. Here we demonstrate that ...glycosylphosphatidylinositol-anchored cell-surface receptors of the Nogo Receptor family (NgR1, NgR2, and NgR3) restrict excitatory synapse formation. Loss of any one of the NgRs results in an increase in synapse number in vitro, whereas loss of all three is necessary for abnormally elevated synaptogenesis in vivo. We show that NgR1 inhibits the formation of new synapses in the postsynaptic neuron by signaling through the coreceptor TROY and RhoA. The NgR family is downregulated by neuronal activity, a response that may limit NgR function and facilitate activity-dependent synapse development. These findings suggest that NgR1, a receptor previously shown to restrict axon growth in the adult, also functions in the dendrite as a barrier that limits excitatory synapse number during brain development.
► Analysis of synaptic development in NgR1−/−, NgR2−/−, and NgR3−/− triple knockout mice ► Identification of a role for the NgR family in the dendrite ► The NgR family restricts dendritic and synaptic growth through TROY and RhoA ► The NgR family is downregulated by neuronal activity both in vitro and in vivo
Wills et al. demonstrate a role for the Nogo Receptor family in postsynaptic neurons in restricting excitatory synapse formation. NgR1 is activity regulated and inhibits the formation of new synapses in the postsynaptic neuron by signaling through the receptors TROY and RhoA.
Driven by the concerns over the dwindling supplies of petroleum and the dire consequences of global warming, the emergence of a hydrogen economy appears inevitable. Such development will require the ...advancement of separation technologies with significantly improved energy and cost efficiencies. Membrane technology is the ideal choice for hydrogen purification due to its lower power usage and costs, simplicity in operation, as well as compactness and portability. Assuming hydrogen purity requirements of <99.5% and relatively modest operating temperatures, polymeric membranes are preferred among the various alternatives. Generally, polymeric membranes for hydrogen enrichment are either H
2- or CO
2-selective, depending on the governing kinetic or thermodynamic factors. In this review, the current state-of-the-art for polymeric membranes applicable to hydrogen purification is considered, and the different approaches for enhancing intrinsic gas-separation performance are evaluated. An assessment of the benefits and shortcomings of the respective membrane types are presented, and the future directions most promising for the development of robust and high-performance polymeric membranes for the hydrogen economy are highlighted.
Thin film composite (TFC) membranes are critical components for reverse osmosis (RO) and nanofiltration (NF) processes. Similar to other liquid-based filtration membranes, TFC membranes are ...susceptible to concentration polarization and fouling/scaling. Recently, surface topography modification has been shown as a potential approach for fouling mitigation. However, for TFC membranes, tailoring the surface topography remains a challenge. Here, we demonstrate for the first time, successful fabrication of a patterned TFC membrane. A two-step fabrication process was carried out by (1) nanoimprinting a polyethersulfone (PES) support, and (2) forming a thin dense film atop the PES support via interfacial polymerization (IP) with trimesoyl chloride and 1,3-phenylenediamine solutions. Chemical, topographic, and permeation characterization was performed on the imprinted IP membranes, and their permselectivity was compared with that of a flat (non-imprinted) TFC membrane prepared using the same IP procedure.
TFC membrane was fabricated for the first time by interfacial polymerization on nanoimprinted ultrafiltration membrane. Topographic, chemical and permselective properties of the surface patterned TFC membrane were characterized systematically. Display omitted
•Thin film composite membrane was synthesized by interfacial polymerization on nanoimprinted ultrafiltration membrane.•The patterned TFC membrane has a permselectivity between typical RO and NF TFC membranes.•Surface pattern can reduce concentration polarization and scaling during salt solution filtration.
•Surface patterning of polymer membranes can be an effective strategy to improve the device performances.•Both porous and dense membranes can be patterned via templated-based micro-molding and direct ...printing methods.•Patterned membrane-electrode assembly can enlarge the active surface area and form more effective ion conduction pathways.•Presence of surface pattern can enhance the shear at the porous membrane surface during separation, which can benefit fouling mitigation.
In recent years, surface patterning of membranes has been explored as a new strategy to modify surface properties of polymeric membranes. A variety of methods including template-based micromolding and direct printing have been developed for effective fabrication of surface-patterned membranes. In this review, we compare the underlying pattern replication mechanisms and the advantages and challenges associated with the range of different fabrication methods. The presence of the surface patterns, when properly created, can enlarge the active surface/interfacial area, create more effective conduction pathways, and enhance the hydrodynamic effects. These effects can be harnessed for improving membrane performance for a wide range of applications.
Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 ...is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation, we provide evidence that the pruritic phenotype in Bhlhb5 mutants is due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritis, and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.
► Mice lacking Bhlhb5 have heightened itch responses and develop skin lesions ► Conditional ablation suggests involvement of spinal inhibitory interneurons ► Bhlhb5 is required for the survival of specific subsets of neurons in the dorsal horn ► Itch can be caused by disinhibition
Shape memory polymers (SMPs) can retain a temporary shape after pre-deformation at an elevated temperature and subsequent cooling to a lower temperature. When reheated, the original shape can be ...recovered. Relatively little work in the literature has addressed the constitutive modeling of the unique thermomechanical coupling in SMPs. Constitutive models are critical for predicting the deformation and recovery of SMPs under a range of different constraints. In this study, the thermomechanics of shape storage and recovery of an epoxy resin is systematically investigated for small strains (within ±10%) in uniaxial tension and uniaxial compression. After initial pre-deformation at a high temperature, the strain is held constant for shape storage while the stress evolution is monitored. Three cases of heated recovery are selected: unconstrained free strain recovery, stress recovery under full constraint at the pre-deformation strain level (no low temperature unloading), and stress recovery under full constraint at a strain level fixed at a low temperature (low temperature unloading). The free strain recovery results indicate that the polymer can fully recover the original shape when reheated above its glass transition temperature (
T
g). Due to the high stiffness in the glassy state (
T
<
T
g), the evolution of the stress under strain constraint is strongly influenced by thermal expansion of the polymer. The relationship between the final recoverable stress and strain is governed by the stress–strain response of the polymer above
T
g. Based on the experimental results and the molecular mechanism of shape memory, a three-dimensional small-strain internal state variable constitutive model is developed. The model quantifies the storage and release of the entropic deformation during thermomechanical processes. The fraction of the material freezing a temporary entropy state is a function of temperature, which can be determined by fitting the free strain recovery response. A free energy function for the model is formulated and thermodynamic consistency is ensured. The model can predict the stress evolution of the uniaxial experimental results. The model captures differences in the tensile and compressive recovery responses caused by thermal expansion. The model is used to explore strain and stress recovery responses under various flexible external constraints that would be encountered in applications of SMPs.
Surface roughness of membranes is often perceived by many as a factor that promotes fouling during filtration, and thus is undesirable. Almost all liquid-based separation membranes display flat ...surfaces with an intrinsic surface roughness that is associated with the membrane manufacturing process. Recently, polymer ultrafiltration and thin film composite membranes containing regular, periodic surface patterns were fabricated using cost-effective lithographic methods. Here, we review the work to date on the fabrication and characterization of these patterned membranes with a focus on processing-structure-performance relationships. In addition, the antifouling performance of these membranes against model foulants including colloidal suspensions and protein solutions is also highlighted.
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