A Fabricated Force Glove That Measures Hand Forces during Activities of Daily Living.

Understanding hand and wrist forces during activities of daily living (ADLs) are pertinent when modeling prosthetics/orthotics, preventing workplace-related injuries, and understanding movement patterns that make athletes, dancers, and musicians elite. The small size of the wrist, fingers, and numerous joints creates obstacles in accurately measuring these forces. In this study, 14 FlexiForce sensors were sewn into a glove in an attempt to capture forces applied by the fingers. Participants in this study wore the glove and performed grasp and key turn activities. The maximal forces produced in the study were 9 N at the distal middle finger phalanx and 24 N at the distal thumb phalanx, respectively, for the grasp and key turn activities. Results from this study will help in determining the minimal forces of the hand during ADLs so that appropriate actuators may be placed at the appropriate joints in exoskeletons, orthotics, and prosthetics.

A Wearable Pulse Oximeter With Wireless Communication and Motion Artifact Tailoring for Continuous Use.

Advances in several engineering fields have led to a trend toward miniaturization and portability of wearable biosensing devices, which used to be confined to large tools and clinical settings. Various systems to continuously measure electrophysiological activity through electrical and optical methods are one category of such devices. Being wearable and intended for prolonged use, the amount of noise introduced on sensors by movement remains a challenge and requires further optimization. User movement causes motion artifacts that alter the overall quality of the signals obtained, hence corrupting the resulting measurements. This paper introduces a fully wearable optical biosensing system to continuously measure pulse oximetry and heart rate, utilizing a reflectance-based probe. Furthermore, a novel data-dependent motion artifact tailoring algorithm is implemented to eliminate noisy data due to the motion artifact and measure oxygenation level with high accuracy in real time. By taking advantages of current wireless transmission and signal processing technologies, the developed wearable photoplethysmography device successfully captures the measured signals and sends them wirelessly to a mobile device for signal processing in real time. After applying motion artifact tailoring, evaluating accuracy with a continuous clinical device, the blood oxygenation measurements obtained from our system yielded an accuracy of at least 98%, when compared to a range of 93.6%-96.7% observed before from the same initial data. Additionally, heart rate accuracy above 97% was achieved. Motion artifact tailoring and removal in real time, continuous systems will allow wearable devices to be truly wearable and a reliable electrophysiological monitoring and diagnostics tool for everyday use.

Novel tailoring algorithm for abrupt motion artifact removal in photoplethysmogram signals.

Photoplethysmogram (PPG) signals are widely used for wearable electronic devices nowadays. The PPG signal is extremely sensitive to the motion artifacts (MAs) caused by the subject's movement. The detection and removal of such MAs remains a difficult problem. Due to the complicated MA signal waveforms, none of the existing techniques can lead to satisfactory results. In this paper, a new framework to identify and tailor the abrupt MAs in PPG is proposed, which consists of feature extraction, change-point detection, and MA removal. In order to achieve the optimal performance, a data-dependent frame-size determination mechanism is employed. Experiments for the heart-beat-rate-measurement application have been conducted to demonstrate the effectiveness of our proposed method, by a correct detection rate of MAs at 98% and the average heart-beat-rate tracking accuracy above 97%. On the other hand, this new framework maintains the original signal temporal structure unlike the spectrum-based approach, and it can be further applied for the calculation of blood oxygen level (SpO2).

Cerebellin 4, a synaptic protein, enhances inhibitory activity and resistance of neurons to amyloid-ß toxicity.

Imbalances between excitatory and inhibitory transmissions in the brain anticipate the neuronal damage and death that occur in the neurodegenerative diseases like Alzheimer's disease (AD). We previously showed that amyloid-ß (Aß), a natural peptide involved in the onset and development of AD, counteracts the neurotrophic activity of the nerve growth factor (NGF) by dampening the γ-aminobutyric acid (GABA)ergic connectivity of cultured hippocampal neurons. Neuronal plasticity is partly controlled by the NGF-promoted expression of the homologue of enhancer-of-split 1 (Hes1), a transcription factor that regulates the formation of GABAergic synapses. We now show that Hes1 controls the expression of cerebellin 4 (Cbln4), a member of a small family of secreted synaptic proteins, and we present the evidence that Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections. Cbln4 immunoreactivity was found in the hippocampus, mostly in the dendrites and somata of pyramidal neurons. In the CA1, the hippocampal region where the first neurons degenerate in AD, Cbln4 immunoreactivity was associated with GABAergic synapses (detected by vesicular inhibitory amino acid transporter [VGAT] immunostaining), which appear to surround and embrace the somata of CA1 pyramidal neurons (basket cells). Moreover, significant decreases of Hes1, Cbln4, and VGAT immunoreactivities and messenger RNA expression were found in the hippocampus of a mouse model of AD. We also found that either the overexpression of Cbln4 in cultured hippocampal neurons or the application of recombinant Cbln4 to the cultures increased the number of GABAergic varicosities, rescuing neurons from Aß-induced death. In contrast, knockdown of Cbln4 gene in cultured neurons was followed by a large reduction of GABAergic connections. Such an effect was reverted by exogenously added Cbln4. These findings suggest a therapeutic potential for Cbln4 in the treatment of AD.

Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL.

APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signaling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3ß in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3ß and the expression of a constitutively active form of GSK-3ß. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3ß signaling.

Growth differentiation factor 5 is a key physiological regulator of dendrite growth during development.

Dendrite size and morphology are key determinants of the functional properties of neurons. Here, we show that growth differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) subclass of the transforming growth factor ß superfamily with a well-characterised role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal cell dendrites in the developing hippocampus. Pyramidal cells co-express GDF5 and its preferred receptors, BMP receptor 1B and BMP receptor 2, during development. In culture, GDF5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends on activation of SMADs 1/5/8 and upregulation of the transcription factor HES5. In vivo, the apical and basal dendritic arbours of pyramidal cells throughout the hippocampus were markedly stunted in both homozygous and heterozygous Gdf5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF5 synthesis.

Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of ß-amyloid (Aß) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of Aß on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor κB (NF-κB) by impeding the tyrosine phosphorylation of I-κBα. As a result, the expression of the homologue of Enhancer-of split 1 (Hes1) gene is downregulated and ultimately, gamma-aminobutyric acid (GABA)-ergic connectivity is lost. METHODS: Hes1 activity was promoted in cultured hippocampal neurons by overexpressing a Hes1-encoding plasmid or by upregulating this gene by activating NF-κB through different approaches (overexpressing either the I-κB kinaseß, or p65/RelA/NF-κB). Alternatively neurons were exposed to TGFß1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-κB activation was measured using the dual-luciferase reporter assay. RESULTS: The expression of Hes1 abolished the effects of Aß on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGFß1, a known neuroprotector, could counteract the deleterious effects of Aß by inducing NF-κB activation following the serine phosphorylation of I-κBα. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. CONCLUSION: Our data define some of the mechanisms involved in Aß-mediated cell death and they point to potential means to counteract this noxious activity.

Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid ß toxicity.

BACKGROUND: Amyloid beta (Aß) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Aß. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Aß. RESULTS: We show here that Aß activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aß. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aß. In addition, over-expression of PTP1B also prevents the deleterious effects of Aß on cultured hippocampal neurons. CONCLUSION: Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aß in Alzheimer's disease.

NGF-activated protein tyrosine phosphatase 1B mediates the phosphorylation and degradation of I-kappa-Balpha coupled to NF-kappa-B activation, thereby controlling dendrite morphology.

NGF diminishes dendrite complexity in cultured hippocampal neurons by decreasing the number of primary and secondary dendrites, while increasing the length of those that remain. The transduction pathway used by NGF to provoke dendrite elongation involves the activation of NF-kappa-B and the expression of the homologues of Enhancer-of-split 1 gene. Here, we define important steps that link NGF with NF-kappa-B activation, through the activity of protein tyrosine phosphatase 1B (PTP1B). Binding of NGF to p75(NTR) stimulates PTP1B activity, which can be blocked by either pharmacological inhibition of the phosphatase or by transfecting neurons with a dn PTP1B isoform, whereby NGF is no longer able to stimulate dendrite growth. Indeed, overexpressing PTP1B alone provoked dendrite growth and further studies revealed a role for the src kinase downstream of PTP1B. Again, loss of src activity largely cancelled out the capacity of NGF to promote dendrite growth, whereas overexpression of v-src in neurons was sufficient to promote dendrite growth. Finally, the NGF/p75(NTR)/PTP1B/src kinase pathway led to the tyrosine phosphorylation of I-kappa-Balpha prior to its degradation, an event that is necessary for NF-kappa-B activation. Indeed, the dendrite growth response to NGF was lost when neurons were transfected with a mutant form of I-kappa-Balpha that lacks tyr42. Thus, our data suggest that PTP1B fulfils a central role in the NGF signalling that controls dendrite patterning in hippocampal neurons.

Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration.

In the nervous system, both the shape and connectivity of neurons are strongly influenced by soluble, extracellular factors. Indeed, we recently demonstrated that after binding to p75(NTR), the common neurotrophin receptor, nerve growth factor (NGF) controls the morphology and connectivity of cultured mouse hippocampal neurons by encouraging the production of fewer yet longer dendrites, and by augmenting GABAergic connectivity. These effects of NGF are mediated by the differential expression of Enhancer-of-split 1/5 homologs and neurogenin 3. Amyloid beta (Abeta), a pathogenic agent in Alzheimer's disease (AD) is known to bind to p75(NTR), hence we studied its influence on cultured hippocampal neurons. At 800 nM, Abeta(1-40) prevents NGF-induced activation of NF-kappaB and consequently, it depresses the expression of Enhancer-of-split 1. Thus, at this concentration, the effect of Abeta on neurons is antagonistic to those provoked by NGF and accordingly, neurons sprout more yet shorter dendrites and their GABAergic input decreases. In contrast, at lower concentration, 20 nM, the amyloid induces cellular effects similar to those induced by NGF, both in terms of gene expression, neuronal morphology, and GABAergic connectivity. Our results demonstrate that Abeta may act as a neurotrophic factor that mimics the activity of NGF. However, at higher concentrations, the amyloid behaves as an antagonist of NGF, contributing to the advent of AD.