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The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer’s disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD., Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.

Si-based electrolyte-gated transistors (EGTs) have been investigated to achieve high sensitivity and a low detection limit (LOD). Here, a lumped-capacitive model was applied to analyze the influence of receptor–target conjugates on the sensing performance. The voltage-related sensitivity is mainly determined by the effective dipole potential ( $V_{DP,EFF}$ ), the effective capacitance of the functionalization layer ( $C_{FN,EFF}$ ), and the total charge density in the channel ( $Q_{S}$ ) related to the operating regime. In an n-type EGT, the sensitivity is enhanced as the device is operated in the subthreshold regime with a positive $V_{DP,EFF}$ and a small $C_{FN,EFF}$ . The influence of the $V_{DP,EFF}$ and $C_{FN,EFF}$ was experimentally evaluated by detecting the peanut allergen (PA) using the fabricated n-type Si-EGTs. A higher sensitivity and a lower LOD could be achieved in the subthreshold regimes than in the linear regime. These results suggest that the proposed model is very useful to optimize the sensing characteristics of Si-based EGT for biosensing applications.

Background Host tp53 mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. Results We found that zebrafish tp53 mutant larvae exhibited elevated intestinal inflammation, by monitoring the NFκB activity in the mid-distal intestines of zebrafish larvae using an NFκB:EGFP transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis, Aeromonas spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in tp53 mutants. Importantly, the ex-germfree experiments supported the causality of the host tp53 mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. Conclusions These results demonstrate a crucial role for host tp53 in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a tp53 mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for tp53 mutation-induced dysbiosis, inflammation, and ultimately, related cancers.

The failure of amyloid beta (Aβ) clearance is a major cause of Alzheimer’s disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, but Aβ clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled Aβ42 to investigate the role of BLECs in Aβ clearance. We discovered the efficient clearance of monomeric Aβ42 (mAβ42) compared to oligomeric Aβ42 (oAβ42), which was illustrated by the selective uptake of mAβ42 by BLECs and peripheral transport. The genetic depletion, pharmacological inhibition via the blocking of the mannose receptor, or the laser ablation of BLECs resulted in the defective clearance of mAβ42. The treatment with an Aβ disaggregating agent facilitated the internalization of oAβ42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mAβ42 from the brain and provide a novel therapeutic strategy based on promoting Aβ clearance.

Visual Abstract, In recent years there has been extensive research on malformations of cortical development (MCDs) that result in clinical features like developmental delay, intellectual disability, and drug-resistant epilepsy (DRE). Various studies highlighted the contribution of microtubule-associated genes (including tubulin and kinesin encoding genes) in MCD development. It has been reported that de novo mutations in KIF2A, a member of the kinesin-13 family, are linked to brain malformations and DRE. Although it is known that KIF2A functions by regulating microtubule depolymerization via an ATP-driven process, in vivo implications of KIF2A loss of function remain partly unclear. Here, we present a novel kif2a knock-out zebrafish model, showing hypoactivity, habituation deficits, pentylenetetrazole-induced seizure susceptibility and microcephaly, as well as neuronal cell proliferation defects and increased apoptosis. Interestingly, kif2a−/− larvae survived until adulthood and were fertile. Notably, our kif2a zebrafish knock-out model demonstrated many phenotypic similarities to KIF2A mouse models. This study provides valuable insights into the functional importance of kif2a in zebrafish and phenotypical hallmarks related to KIF2A mutations. Ultimately, this model could be used in a future search for more effective therapies that alleviate the clinical symptoms typically associated with MCDs.

During chronic cold stress, thermogenic adipocytes generate heat through uncoupling of mitochondrial respiration from ATP synthesis. Recent discovery of various dietary phytochemicals, endogenous metabolites, synthetic compounds, and their molecular targets for stimulating thermogenesis has provided promising strategies to treat or prevent obesity and its associated metabolic diseases. Nuclear factor E2 p45-related factor 2 (Nrf2) is a stress response protein that plays an important role in obesity and metabolisms. However, both Nrf2 activation and Nrf2 inhibition can suppress obesity and metabolic diseases. Here, we summarized and discussed conflicting findings of Nrf2 activities accounting for part of the variance in thermogenesis and energy metabolism. We also discussed the utility of Nrf2-activating mechanisms for their potential applications in stimulating energy expenditure to prevent obesity and improve metabolic deficits.

Patient-controlled epidural analgesia is widely used to control postoperative pain following major intra-abdominal surgeries. However, determining the optimal infusion dose that can produce effective analgesia while reducing side effects remains a task to be solved. Postoperative pain and adverse effects between variable-rate feedback infusion (VFIM group, n = 36) and conventional fixed-rate basal infusion (CFIM group, n = 36) of fentanyl/ropivacaine-based patient-controlled epidural analgesia were evaluated. In the CFIM group, the basal infusion rate was fixed (5 mL/h), whereas, in the VFIM group, the basal infusion rate was increased by 0.5 mL/h each time a bolus dose was administered and decreased by 0.3 mL/h when a bolus dose was not administered for 2 h. Patients in the VFIM group experienced significantly less pain at one to six hours after surgery than those in the CFIM group. Further, the number of patients who suffered from postoperative nausea was significantly lower in the VFIM group than in the CFIM group until six hours after surgery. The variable-rate feedback infusion mode of patient-controlled epidural analgesia may provide better analgesia accompanied with significantly less nausea in the early postoperative period than the conventional fixed-rate basal infusion mode following open gastrectomy.

Olfaction is an important neural system for survival and fundamental behaviors such as predator avoidance, food finding, memory formation, reproduction, and social communication. However, the neural circuits and pathways associated with the olfactory system in various behaviors are not fully understood. Recent advances in optogenetics, high-resolution in vivo imaging, and reconstructions of neuronal circuits have created new opportunities to understand such neural circuits. Here, we generated a transgenic zebrafish to manipulate olfactory signal optically, expressing the Channelrhodopsin (ChR2) under the control of the olfactory specific promoter, omp. We observed light-induced neuronal activity of olfactory system in the transgenic fish by examining c-fos expression, and a calcium indicator suggesting that blue light stimulation caused activation of olfactory neurons in a non-invasive manner. To examine whether the photo-activation of olfactory sensory neurons affect behavior of zebrafish larvae, we devised a behavioral choice paradigm and tested how zebrafish larvae choose between two conflicting sensory cues, an aversive odor or the naturally preferred phototaxis. We found that when the conflicting cues (the preferred light and aversive odor) were presented together simultaneously, zebrafish larvae swam away from the aversive odor. However, the transgenic fish with photo-activation were insensitive to the aversive odor and exhibited olfactory desensitization upon optical stimulation of ChR2. These results show that an aversive olfactory stimulus can override phototaxis, and that olfaction is important in decision making in zebrafish. This new transgenic model will be useful for the analysis of olfaction related behaviors and for the dissection of underlying neural circuits.

The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer's disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.

We present the fabrication and electrical characteristics of nanonet-channel (NET) low-temperature polysilicon channel (LTPS) thin-film transistors (TFTs) using a nanosphere-assisted patterning (NAP) technique. The NAP technique is introduced to form a nanonet-channel instead of the electron beam lithography (EBL) or conventional photolithography method. The size and space of the holes in the nanonet structure are well controlled by oxygen plasma treatment and a metal lift-off process. The nanonet-channel TFTs show improved electrical characteristics in terms of the ION/IOFF, threshold voltage, and subthreshold swing compared with conventional planar devices. The nanonet-channel devices also show a high immunity to hot-carrier injection and a lower variation of electrical characteristics. The standard deviation of VTH (σVTH) is reduced by 33% for a nanonet-channel device with a gate length of 3 μm, which is mainly attributed to the reduction of the grain boundary traps and enhanced gate controllability. These results suggest that the cost-effective NAP technique is promising for manufacturing high-performance nanonet-channel LTPS TFTs with lower electrical variations.

Background DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. Methods We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. Results Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. Conclusions In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes.

In this study, we employ a combination of various in-situ surface analysis techniques to investigate the thermally induced degradation processes in MAPbI3 perovskite solar cells (PeSCs) as a function of temperature under air-free conditions (no moisture and oxygen). Through a comprehensive approach that combines in-situ grazing-incidence wide-angle X-ray diffraction (GIWAXD) and high-resolution X-ray photoelectron spectroscopy (HR-XPS) measurements, we confirm that the surface structure of MAPbI3 perovskite film changes to an intermediate phase and decomposes to CH3I, NH3, and PbI2 after both a short (20 min) exposure to heat stress at 100 °C and a long exposure (>1 hour) at 80 °C. Moreover, we observe clearly the changes in the orientation of CH3NH3+ organic cations with respect to the substrate in the intermediate phase, which might be linked directly to the thermal degradation processes in MAPbI3 perovskites. These results provide important progress towards improved understanding of the thermal degradation mechanisms in perovskite materials and will facilitate improvements in the design and fabrication of perovskite solar cells with better thermal stability.

We report the electrical characteristics and pH responses of a Si-nanonet ion-sensitive field-effect transistor with ultra-thin parylene-H as a gate sensing membrane. The fabricated device shows excellent DC characteristics: a low subthreshold swing of 85 mV/dec, a high current on/off ratio of ~107 and a low gate leakage current of ~10&minus, 10 A. The low interface trap density of 1.04 &times, 1012 cm&minus, 2 and high field-effect mobility of 510 cm2V&minus, 1s&minus, 1 were obtained. The pH responses of the devices were evaluated in various pH buffer solutions. A high pH sensitivity of 48.1 &plusmn, 0.5 mV/pH with a device-to-device variation of ~6.1% was achieved. From the low-frequency noise characterization, the signal-to-noise ratio was extracted as high as ~3400 A/A with the lowest noise equivalent pH value of ~0.002 pH. These excellent intrinsic electrical and pH sensing performances suggest that parylene-H can be promising as a sensing membrane in an ISFET-based biosensor platform.

A silver nanoparticle is one of the representative engineered nanomaterials with excellent optical, electrical, antibacterial properties. Silver nanoparticles are being increasingly used for medical products, water filters, and cosmetics, etc. However, silver nanoparticles are known to cause adverse effects on the ecosystem and human health. To utilize silver nanoparticles with minimized negative effects, it is important to understand the behavior of silver nanoparticles released to the environment. In this study, we compared toxicity behaviors of citrate-stabilized silver nanoparticles with polyethylene glycol coated silver nanoparticles in two different ionic environments, which are aquatic environments for developing zebrafish embryo. Depending on the composition of the ionic environment, citrate-stabilized silver nanoparticles and polyethylene glycol coated silver nanoparticles exhibited different behaviors in dissolution, aggregation, or precipitation, which governed the toxicity of silver nanoparticles on zebrafish embryos.

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors such as neuroblastoma in DS patients and increased vascular anomalies in DS fetuses suggest a potential role of DYRK1A in angiogenic processes, but in vivo evidence is still scarce. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that DYRK1A plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases., Summary: The roles of DYRK1A in angiogenesis and maintenance of the developing cerebral vasculature mediated by calcium signaling were revealed using zebrafish dyrk1aa knockout mutants.

Fluorescent polydopamine nanoparticles (FPNPs) are prepared via the ethylenediamine (EDA)-induced degradation of as-prepared non-fluorescent polydopamine (PDA) and used for targeted bioimaging. The reductive treatment of PDA in the presence of EDA yields fluorescent precipitates, inspiring us to seek various biological approaches to preparing FPNPs with excellent optical and biocompatible properties. Moreover, we firstly found that FPNPs selectively label neuromast hair cells in the lateral line of zebrafish, their applications as a reliable fluorescent indicator to investigate the neuromast hair cells, to in turn determine the viability of hair cells, was demonstrated. FPNPs also provided a minimal toxicity enable to assay the number of functional hair cells per neuromast in live animals as development proceeds. Upon combined incubation with TO-PRO-3, a well-established hair cell marker, all hair cells that were rapidly labeled with FPNPs were observed to be also completely labeled with the TO-PRO-3, labeling hair cells in neuromasts positioned in the supraorbital, otic and occipital lateral line as well as in posterior lateral line of living zebrafish larvae. Their potential efficacy for biological applications was demonstrated by their excellent optical and biocompatible properties, offering new opportunities in cancer research, real-time monitoring of stem cell transplantation and other cell-based therapies.

When considering the principles of a pain control strategy by patients, reliable administration of additional bolus doses is important for providing the adequate analgesia and improving patient satisfaction. We compared the efficacy of elastomeric patient-control module (PCM) with conventional PCM providing epidural analgesia postoperatively. A noninferiority comparison was used. Eighty-six patients scheduled for open upper abdominal surgery were randomized to use either an elastomeric or conventional PCM connected to balloon pump. After successful epidural catheter insertion at T6–8 level, fentanyl (15–20 μg/kg) in 0.3% ropivacaine 100 mL was administered at basal rate 2 mL/h with bolus 2 mL and lock-out time 15 minutes. The primary outcome was the verbal numerical rating score for pain. The 95% confidence intervals for differences in pain scores during the first 48 hours postoperatively were

Background: Aging causes profound changes of stiffness and compliance in the cardiovascular system, which contributes to decreased cardiovascular reserve. Mechanisms of the underlying endothelial vasodilator dysfunction in vasodilator signaling pathways may occur at multiple sites within any of these pathways. Methods: Age-related changes in the vasculature were investigated in adult young (3-6 months, Y) and old (2629 month, O) Wistar rats (n = 6). The aortas were carefully dissected from the rat and cut into rings 1.5 -2.0 mm in length to measure in vitro isometric tension. Vasorelaxant responses of aortic rings to acetylcholine (ACh), sodium nitroprusside (SNP) and P1075 were examined using Dose Response software (AD Instruments, Mountain View, CA). Results: Endothelium-dependent vasodilator function was impaired. The endothelium of aging rats impaired endothelial NO dependent vasodilation, but the machinery for vasodilation was not impaired. Conclusions: Age-related NO-mediated vasorelaxation in the aging endothelium was inhibited and appears to be major mechanism of vascular change and impaired vascular regulation. (Korean J Anesthesiol 2011; 61: 506-510)

Pulsed radiofrequency (PRF) treatment of nervous tissue has been proposed as a less neurodestructive technique alternative to continuous RF heat lesioning. Recently, clinical reports using PRF have shown favorable effects in the treatment of a variety of focal pain areas, even in non-nervous tissues; however, the mechanism of effect underlying this treatment to non-nervous tissue remains unclear. We report the case of a 67-year-old male who presented with pain reliving point in the posterior neck. The patient had pain in the posterior neck for 3 years. The pain subsided with pressure applied to a point in the posterior neck. There were no specific abnormal findings on laboratory testing and radiologic examinations. After PRF treatment to the pain-relieving point, he had pain relief which lasted more than 5 months.

Background: Valvular heart surgery (VHS) utilizing cardiopulmonary bypass (CPB) is inevitably associated with ischemic-reperfusion injury, which is known to depend on oxygen tension during reperfusion. The aim of this study was to evaluate the effect of arterial oxygen tension during reperfusion on myocardial recovery in patients undergoing VHS. Methods: Fifty-six patients undergoing isolated VHS were randomly exposed to an oxygen fraction of 0.7 (hyperoxic group, n = 28) or 0.5 (normoxic group, n = 28) during reperfusion. All patients received an oxygen fraction of 0.7 during CPB. In the normoxic group, the oxygen fraction was lowered to 0.5 from the last warm cardioplegia administration to 1 minute after aortic unclamping, and was then raised back to 0.7. Hemodynamic data were measured after induction of anesthesia, weaning from CPB, and sternum closure. The frequency of cardiotonic medications used during and after weaning from CPB, and the short-term outcomes during the hospital stay were also assessed. Results: The frequency of vasopressin and milrinone use during weaning from CPB, but not norepinephrine, was significantly less in the normoxic group. The post-operative cardiac enzyme levels and short-term outcomes were not different between the groups. Conclusions: Normoxic reperfusion from the last cardioplegia administration to 1 minute after aortic unclamping in patients undergoing VHS resulted in significantly less frequent use of vasopressin and inotropics during weaning from CPB than hyperoxic reperfusion, although it did not affect the post-operative myocardial enzyme release or short-term prognosis.

Background The honey bee is an important model system for increasing understanding of molecular and neural mechanisms underlying social behaviors relevant to the agricultural industry and basic science. The western honey bee, Apis mellifera, has served as a model species, and its genome sequence has been published. In contrast, the genome of the Asian honey bee, Apis cerana, has not yet been sequenced. A. cerana has been raised in Asian countries for thousands of years and has brought considerable economic benefits to the apicultural industry. A cerana has divergent biological traits compared to A. mellifera and it has played a key role in maintaining biodiversity in eastern and southern Asia. Here we report the first whole genome sequence of A. cerana. Results Using de novo assembly methods, we produced a 238 Mbp draft of the A. cerana genome and generated 10,651 genes. A.cerana-specific genes were analyzed to better understand the novel characteristics of this honey bee species. Seventy-two percent of the A. cerana-specific genes had more than one GO term, and 1,696 enzymes were categorized into 125 pathways. Genes involved in chemoreception and immunity were carefully identified and compared to those from other sequenced insect models. These included 10 gustatory receptors, 119 odorant receptors, 10 ionotropic receptors, and 160 immune-related genes. Conclusions This first report of the whole genome sequence of A. cerana provides resources for comparative sociogenomics, especially in the field of social insect communication. These important tools will contribute to a better understanding of the complex behaviors and natural biology of the Asian honey bee and to anticipate its future evolutionary trajectory. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-16-1) contains supplementary material, which is available to authorized users.

International audience; Bio-nanosensors and communication at the nanoscale are a promising paradigm and technology for the development of a new class of ehealth solutions. While recent communication technologies such as mobile and wireless combined with medical sensors have allowed new successful eHealth applications, another level of innovation is required to deliver scalable and cost-effective solutions via developing devices that operate and communicate directly inside the body. This work presents the application of nano technology for the development of miniaturized bio-nanosensors that are able to communicate and exchange information about sensed molecules or chemical compound concentration and therefore draw a global response in the case of health anomalies. Two communication techniques are reviewed: electromagnetic wireless communication in the terahertz band and molecular communication. The characteristics of these two modes of communication are highlighted, and a general architecture for bio-nanosensors is proposed along with examples of cooperation schemes. An implementation of the bio-nanosensor part of the nanomachine is presented along with some experimental results of sensing biomolecules. Finally, a general example of coordination among bio-nanomachines using both communication technologies is presented, and challenges in terms of communication protocols, data transmission, and coordination among nanomachines are discussed.

SummaryAmplification of the MYCN oncogene in childhood neuroblastoma is often accompanied by mutational activation of ALK (anaplastic lymphoma kinase), suggesting their pathogenic cooperation. We generated a transgenic zebrafish model of neuroblastoma in which MYCN-induced tumors arise from a subpopulation of neuroblasts that migrate into the adrenal medulla analog following organogenesis. Coexpression of activated ALK with MYCN in this model triples the disease penetrance and markedly accelerates tumor onset. MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. Coexpression of activated ALK with MYCN provides prosurvival signals that block this apoptotic response and allow continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma.

SummaryEndoplasmic reticulum (ER) stress triggers tissue-specific responses that culminate in either cellular adaptation or apoptosis, but the genetic networks distinguishing these responses are not well understood. Here we demonstrate that ER stress induced in the developing zebrafish causes rapid apoptosis in the brain, spinal cord, tail epidermis, lens, and epiphysis. Focusing on the tail epidermis, we uncover an apoptotic response that depends on Puma, but not on p53 or Chop. puma is transcriptionally activated during this ER stress response in a p53-independent manner, and is an essential mediator of epidermal apoptosis. We demonstrate that the p63 transcription factor is upregulated to initiate this apoptotic pathway and directly activates puma transcription in response to ER stress. We also show that a mutation of human Connexin 31, which causes erythrokeratoderma variabilis, induces ER stress and p63-dependent epidermal apoptosis in the zebrafish embryo, thus implicating this pathway in the pathogenesis of inherited disease.

International audience; A new generation of a ubiquitous health smart home is being developed to support the elderly and/or people with chronic diseases in their own home. The goal of the U-Health smart home is to help the elderly to continue to live a more independent life as long as possible in their own home while being monitored and assisted in an unobtrusive manner. This concept of a ubiquitous health care (U-Health) smart home for the elderly has been identified by governments and medical institutions as an important part of the economical, technological, and socially acceptable solution to maintain the health welfare system viable for future generation.

Neurofibromatosis type 1 is the most commonly inherited human cancer predisposition syndrome. Neurofibromin (NF1) gene mutations lead to increased risk of neurofibromas, schwannomas, low grade, pilocytic optic pathway gliomas, as well as malignant peripheral nerve sheath tumors and glioblastomas. Despite the evidence for NF1 tumor suppressor function in glial cell tumors, the mechanisms underlying transformation remain poorly understood. In this report, we used morpholinos to knockdown the two nf1 orthologs in zebrafish and show that oligodendrocyte progenitor cell (OPC) numbers are increased in the developing spinal cord, whereas neurons are unaffected. The increased OPC numbers in nf1 morphants resulted from increased proliferation, as detected by increased BrdU labeling, whereas TUNEL staining for apoptotic cells was unaffected. This phenotype could be rescued by the forced expression of the GTPase-activating protein (GAP)-related domain of human NF1. In addition, the in vivo analysis of OPC migration following nf1 loss using time-lapse microscopy demonstrated that olig2-EGFP(+) OPCs exhibit enhanced cell migration within the developing spinal cord. OPCs pause intermittently as they migrate, and in nf1 knockdown animals, they covered greater distances due to a decrease in average pause duration, rather than an increase in velocity while in motion. Interestingly, nf1 knockdown also leads to an increase in ERK signaling, principally in the neurons of the spinal cord. Together, these results show that negative regulation of the Ras pathway through the GAP activity of NF1 limits OPC proliferation and motility during development, providing insight into the oncogenic mechanisms through which NF1 loss contributes to human glial tumors.