Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators.

Neuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) and CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking translation to neuronal activity is not understood. We now find that translation is stimulated when FMRP and CYFIP1 translocate to the potassium channel Slack (KCNT1, Slo2.2). When Slack is activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit translation initiation. A constitutively active Slack mutation and pharmacological stimulation of the wild-type channel both increase binding of FMRP and CYFIP1 to the channel, enhancing the translation of a reporter for ß-actin mRNA in cell lines and the synthesis of ß-actin in neuronal dendrites. Slack activity-dependent translation is abolished when both FMRP and CYFIP1 expression are suppressed. The effects of Slack mutations on activity-dependent translation may explain the severe intellectual disability produced by these mutations in humans. HIGHLIGHTS: Activation of Slack channels triggers translocation of the FMRP/CYFIP1 complexSlack channel activation regulates translation initiation of a ß-actin reporter constructA Slack gain-of-function mutation increases translation of ß-actin reporter construct and endogenous cortical ß-actinFMRP and CYFIP1 are required for Slack activity-dependent translation. IN BRIEF: Malone et al . show that the activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex from the translation initiation factor eIF4E to the channel. This translocation releases eIF4E and stimulates mRNA translation of a reporter for ß-actin and cortical ß-actin mRNA, elucidating the mechanism that connects neuronal activity with translational regulation.

Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.

Microfluidic-based processors and circuits design.

Droplets produced within microfluidics have not only attracted the attention of researchers to develop complex biological, industrial and clinical testing systems but also played a role as a bit of data. The flow of droplets within a network of microfluidic channels by stimulation of their movements, trajectories, and interaction timing, can provide an opportunity for preparation of complex and logical microfluidic circuits. Such mechanical-based circuits open up avenues to mimic the logic of electrical circuits within microfluidics. Recently, simple microfluidic-based logical elements such as AND, OR, and NOT gates have been experimentally developed and tested to model basic logic conditions in laboratory settings. In this work, we develop new microfluidic networks, control the shape of channels and speed of droplet movement, and regulate the size of bubbles in order to extend the logical elements to six new logic gates, including AND/OR type 1, AND/OR type 2, NOT type 1, NOT type 2, Flip-Flop, Synchronizer, and a parametric model of T-junction as a bubble generator. We further designed and simulated a novel microfluidic Decoder 1 to 2, a Decoder 2 to 4, and a microfluidic circuit that combines several individual logic gates into one complex circuit. Further fabrication and experimental testing of these newly introduced logic gates within microfluidics enable implementing complex circuits in high-throughput microfluidic platforms for tissue engineering, drug testing and development, and chemical synthesis and process design.

5-Axis CNC Micromilling for Rapid, Cheap, and Background-Free NMR Microcoils.

The superior mass sensitivity of microcoil technology in nuclear magnetic resonance (NMR) spectroscopy provides potential for the analysis of extremely small-mass-limited samples such as eggs, cells, and tiny organisms. For optimal performance and efficiency, the size of the microcoil should be tailored to the size of the mass-limited sample of interest, which can be costly as mass-limited samples come in many shapes and sizes. Therefore, rapid and economic microcoil production methods are needed. One method with great potential is 5-axis computer numerical control (CNC) micromilling, commonly used in the jewelry industry. Most CNC milling machines are designed to process larger objects and commonly have a precision of >25 µm (making the machining of common spiral microcoils, for example, impossible). Here, a 5-axis MiRA6 CNC milling machine, specifically designed for the jewelry industry, with a 0.3 µm precision was used to produce working planar microcoils, microstrips, and novel microsensor designs, with some tested on the NMR in less than 24 h after the start of the design process. Sample wells could be built into the microsensor and could be machined at the same time as the sensors themselves, in some cases leaving a sheet of Teflon as thin as 10 µm between the sample and the sensor. This provides the freedom to produce a wide array of designs and demonstrates 5-axis CNC micromilling as a versatile tool for the rapid prototyping of NMR microsensors. This approach allowed the experimental optimization of a prototype microstrip for the analysis of two intact adult Daphnia magna organisms. In addition, a 3D volume slotted-tube resonator was produced that allowed for 2D 1H-13C NMR of D. magna neonates and exhibited 1H sensitivity (nLODω600 = 1.49 nmol s1/2) close to that of double strip lines, which themselves offer the best compromise between concentration and mass sensitivity published to date.

Analysis of Dynamics Targeting CNT-Based Drug Delivery through Lung Cancer Cells: Design, Simulation, and Computational Approach.

Nowadays, carbon nano (CN) structures and specifically carbon nanotubes (CNTs), because of the nanotube's nanoscale shape, are widely used in carrier and separation applications. The conjugation of CNTs with polysaccharide, proteins, drugs, and magnetic nanoparticles provides a chance for smart targeting and trajectory manipulation, which are used in the crucial field of life science applications, including for cancer disease diagnostics and treatments. Providing an optimal procedure for delivering a drug to a specific area based on mathematical criteria is key in systemic delivery design. Trajectory guidance and applied force control are the main parameters affected by systemic delivery. Moreover, a better understanding of the tissue parameters and cell membrane molecular behaviour are other factors that can be indirectly affected by the targeted delivery. Both sides are an essential part of successful targeting. The lung is one of the challenging organs for drug delivery inside the human body. It has a large surface area with a thin epithelium layer. A few severe diseases directly involve human lung cells, and optimal and successful drug delivery to the lung for the treatment procedure is vital. In this paper, we studied functionalized CNTs' targeted delivery via crossing through the lung cell membrane. Molecular dynamics (MD) software simulated all the interaction forces. Mathematical modelling of the cell membrane and proposed delivery system based on the relation of velocity and force has been considered. Dynamics equations for CNTs were defined in the time and frequency domain using control theory methods. The proposed delivery system consists of two main parts: crossing through the cell membrane and targeting inside the cell. For both steps, a mathematical model and a proper magnetic field profile have been proposed. The designed system provides criteria for crossing through the cell membrane within 30 s to 5 min and a translocation profile of 1 to 100 Å.

Publication Trends in Exosomes Nanoparticles for Cancer Detection.

BACKGROUND: Exosomes are small vesicles produced by almost all cells in the body and found in all biofluids. Cancer cell-derived exosomes are known to have distinct, measurable signatures, applicable for early cancer diagnosis. Despite the present bibliometric studies on "Cancer detection" and "Nanoparticles", no single study exists to deal with "Exosome" bibliometric study. METHODS: This bibliometric work investigated the publication trends of "Exosomes" nanoparticles and its application in cancer detection, for the literature from 2008 to July 2019. The data were collected from the Web of Science Core Collection. There were variant visual maps generated to show annual publication, most- relevant authors, sources, countries, topics and keywords. The network analysis of these studies was investigated to evaluate the research trends in the field of exosomes. In addition, the data were qualitatively analyzed according to 22 top-cited articles, illustrating the frequently used subjects and methods in exosomes research area. RESULTS: The results showed that the documents in this field have improved the citation rate. The top-relevant papers are mostly published in Scientific Reports journal which has lost its popularity after 2017, while today, Analytical Chemistry is leading in publishing the most articles related to exosomes. The documents containing keywords of plasma, cells, cancer, biomarkers, and vesicles as keywords plus, are more likely to be published in PLoS One journal. The clustering of the keywords network showed that the keyword theme of "extracellular vesicles" has the highest centrality rate. In global research, USA is the most corresponding country, followed by China, Korea and Australia. Based on the qualitative analysis, the published documents with at least 50 citations have used exosome release, cargo, detection, purification and secretion, as their targets and applied cell culture or isolation as their methods. CONCLUSION: The bibliometric study on exosomes nanoparticles for cancer detection provides a clear vision of the future research direction and identifies the potential opportunities and challenges. This may lead new researchers to select the proper subfields in exosome-related research fields.

Publication Trends in Drug Delivery and Magnetic Nanoparticles.

This bibliometric study investigated the public trends in the fields of nanoparticles which is limited to drug delivery and magnetic nanoparticles' literature published from 1980 to October 2017. The data were collected from the Web of Science Core Collections, and a network analysis of research outputs was carried out to analyse the research trends in the nanoparticles literature. Nanoparticles and its applications are progressing in recent years. The results show that documents in the field of nanoparticles in chemistry and material science have improved in citation rate, as the authors were researching in multidisciplinary zones. Top-cited documents are mainly focusing on drug delivery, magnetic nanoparticles and iron oxide nanoparticles which are also the top research keywords in all papers published. Top-cited papers are mostly published in Biomaterials journal which so far has published 12% of top-cited articles. Although research areas such as contrast agents, quantum dots, and nanocrystals are not considered as the top-ranked keywords in all documents, these keywords received noticeable citations. The trends of publications on drug delivery and magnetic nanoparticles give a general view on future research and identify potential opportunities and challenges.

An Improved Method for Magnetic Nanocarrier Drug Delivery across the Cell Membrane.

One of the crucial issues in the pharmacological field is developing new drug delivery systems. The main concern is to develop new methods for improving the drug delivery efficiencies such as low disruptions, precise control of the target of delivery and drug sustainability. Nowadays, there are many various methods for drug delivery systems. Carbon-based nanocarriers are a new efficient tool for translocating drug into the defined area or cells inside the body. These nanocarriers can be functionalized with proteins, peptides and used to transport their freight to cells or defined areas. Since functionalized carbon-based nanocarriers show low toxicity and high biocompatibility, they are used in many nanobiotechnology fields. In this study, different shapes of nanocarrier are investigated, and the suitable magnetic field, which is applied using MRI for the delivery of the nanocarrier, is proposed. In this research, based on the force required to cross the membrane and MD simulations, the optimal magnetic field profile is designed. This optimal magnetic force field is derived from the mathematical model of the system and magnetic particle dynamics inside the nanocarrier. The results of this paper illustrate the effects of the nanocarrier's shapes on the percentage of success in crossing the membrane and the optimal required magnetic field.

Optimal Magnetic Field for Crossing Super-Para-Magnetic Nanoparticles through the Brain Blood Barrier: A Computational Approach.

This paper scrutinizes the magnetic field effect to deliver the superparamagnetic nanoparticles (SPMNs) through the Blood Brain Barrier (BBB). Herein we study the interaction between the nanoparticle (NP) and BBB membrane using Molecular Dynamic (MD) techniques. The MD model is used to enhance our understanding of the dynamic behavior of SPMNs crossing the endothelial cells in the presence of a gradient magnetic field. Actuation of NPs under weak magnetic field offers the great advantage of a non-invasive drug delivery without the risk of causing injury to the brain. Furthermore, a weak magnetic portable stimulator can be developed using low complexity prototyping techniques. Based on MD simulation results in this paper, SPMNs can cross the cell membrane while experiencing very weak mechanical forces in the range of pN. This study also derives guidelines for the design of the SPMNs dedicated to crossing the BBB using external magnetic fields.

Toward Epileptic Brain Region Detection Based on Magnetic Nanoparticle Patterning.

Resection of the epilepsy foci is the best treatment for more than 15% of epileptic patients or 50% of patients who are refractory to all forms of medical treatment. Accurate mapping of the locations of epileptic neuronal networks can result in the complete resection of epileptic foci. Even though currently electroencephalography is the best technique for mapping the epileptic focus, it cannot define the boundary of epilepsy that accurately. Herein we put forward a new accurate brain mapping technique using superparamagnetic nanoparticles (SPMNs). The main hypothesis in this new approach is the creation of super-paramagnetic aggregates in the epileptic foci due to high electrical and magnetic activities. These aggregates may improve tissue contrast of magnetic resonance imaging (MRI) that results in improving the resection of epileptic foci. In this paper, we present the mathematical models before discussing the simulation results. Furthermore, we mimic the aggregation of SPMNs in a weak magnetic field using a low-cost microfabricated device. Based on these results, the SPMNs may play a crucial role in diagnostic epilepsy and the subsequent treatment of this disease.

MRI-guided epilepsy detection.

One of the most common neurological brain disorder is epilepsy that happen as an abrupt seizure. Around 30% of patients with epilepsy resist to all forms of medical treatments and, therefore, the removal of epileptic brain tissue is the only solution to get these patients free from chronical seizures. Discovering the epileptic region is a first key into the treatment. In this paper, we introduced a method for epilepsy detection. In this method superparamagnetic nanoparticle, (SPMN) is used as a sensing material in order to investigate the epileptic area. Based on the magnetic field, first they are crossed through the Blood Brain Barrier (BBB). They can cross the blood-brain barrier into the brain by means of magnetic forces. In this study, the optimal force for crossing to the brain and nanoparticles aggregation by means of MRI magnetic field for crossing and weak magnetic field inside the brain have been considered. Nanoparticles aggregation can be used as a marker to increase the contrast of MRI images in the epileptic brain area.

Modeling and simulation of crossing magnetic nanoparticles through blood brain barrier (BBB).

Crossing the Blood Brain Barrier (BBB), despite its tight junctions, is of the great importance in a plethora of medical applications. As a result, this work is dedicated to molecular dynamics (MD) simulation of crossing through the BBB particularly under the effect of magnetic force. For this purpose, two cases of a coated gold nanocparticle with insulin and uncoated gold nanoparticle have been considered; there, the dominant governing parameters in each case are changed to identify the optimized condition for crossing nanoparticles. These parameters are of biological (ligand-receptor binding affinity), biophysical (membrane surface receptor density ratio and non-specific interaction parameter) or geometrical (size of components) origin. The most important part of this study is MD simulation of nanoparticles under the effect of magnetic field and the result shows that for crossing through BBB what force profile must be provided by the magnetic field.

Parameter estimation and interval type-2 fuzzy sliding mode control of a z-axis MEMS gyroscope.

This paper reports a hybrid intelligent controller for application in single axis MEMS vibratory gyroscopes. First, unknown parameters of a micro gyroscope including unknown time varying angular velocity are estimated online via normalized continuous time least mean squares algorithm. Then, an additional interval type-2 fuzzy sliding mode control is incorporated in order to match the resonant frequencies and to compensate for undesired mechanical couplings. The main advantage of this control strategy is its robustness to parameters uncertainty, external disturbance and measurement noise. Consistent estimation of parameters is guaranteed and stability of the closed-loop system is proved via the Lyapunov stability theorem. Finally, numerical simulation is done in order to validate the effectiveness of the proposed method, both for a constant and time-varying angular rate.