A Synthetic Derivative SH 66 of Homoisoflavonoid from Liliaceae Exhibits Anti-Neuroinflammatory Activity against LPS-Induced Microglial Cells.

Naturally occurring homoisoflavonoids isolated from some Liliaceae plants have been reported to have diverse biological activities (e.g., antioxidant, anti-inflammatory, and anti-angiogenic effects). The exact mechanism by which homoisoflavonones exert anti-neuroinflammatory effects against activated microglia-induced inflammatory cascades has not been well studied. Here, we aimed to explore the mechanism of homoisoflavonoid SH66 having a potential anti-inflammatory effect in lipopolysaccharide (LPS)-primed BV2 murine microglial cells. Microglia cells were pre-treated with SH66 followed by LPS (100 ng/mL) activation. SH66 treatment attenuated the production of inflammatory mediators, including nitric oxide and proinflammatory cytokines, by down-regulating mitogen-activated protein kinase signaling in LPS-activated microglia. The SH66-mediated inhibition of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex and the respective inflammatory biomarker-like active interleukin (IL)-1ß were noted to be one of the key pathways of the anti-inflammatory effect. In addition, SH66 increased the neurite length in the N2a neuronal cell and the level of nerve growth factor in the C6 astrocyte cell. Our results demonstrated the anti-neuroinflammatory effect of SH66 against LPS-activated microglia-mediated inflammatory events by down-regulating the NLRP3 inflammasome complex, with respect to its neuroprotective effect. SH66 could be an interesting candidate for further research and development regarding prophylactics and therapeutics for inflammation-mediated neurological complications.

A Microfluidic System for Investigating Anticipatory Medication Effects on Dopamine Homeostasis in Dopaminergic Cells.

Dopamine (DA) homeostasis influences emotions, neural circuit development, cognition, and the reward system. Dysfunctions in DA regulation can lead to neurological disorders, including depression, developmental disorders, and addiction. DA homeostasis disruption is a primary cause of Parkinson's Disease (PD). Therefore, understanding the relationship between DA homeostasis and PD progression may clarify the mechanisms for pharmacologically treating PD. This study developed a novel in vitro DA homeostasis platform which consists of three main parts: (1) a microfluidic device for culturing DAergic neurons, (2) an optical detection system for reading DA levels, and (3) an automatic closed-loop control system that establishes when and how much medication to infuse; this uses a microfluidic device that can cultivate DAergic neurons, perfuse solutions, perform in vitro PD modeling, and continuously monitor DA concentrations. The automatically controlled closed-loop control system simultaneously monitors pharmacological PD treatment to support long-term monitoring of DA homeostasis. SH-SY5Y neuroblastoma cells were chosen as DAergic neurons. They were cultivated in the microfluidic device, and real-time cellular DA level measurements successfully achieved long-term monitoring and modulation of DA homeostasis. When applied in combination with multiday cell culture, this advanced system can be used for drug screening and fundamental biological studies.

Measurement device hacking-free mutual quantum identity authentication over a deployed optical fiber.

Quantum identity authentication serves as a crucial technology for secure quantum communication, but its security often faces challenges due to quantum hacking of measurement devices. This study introduces a measurement-device-independent mutual quantum identity authentication (MDI MQIA) scheme capable of ensuring secure user authentication, despite the use of measurement devices vulnerable to quantum hacking. To realize the MDI MQIA scheme, we proposed and applied a modified Bell state measurement based on linear optics, enabling the probabilistic measurement of all Bell states. Furthermore, the proposed experimental setup adopted a plug-and-play architecture, thus efficiently establishing the indistinguishability of two photons prepared by the communication members. Finally, we successfully performed a proof-of-principle experimental demonstration of the proposed scheme using a field-deployed fiber, achieving quantum bit error rates of less than 3%.

The Anti-Atopic Dermatitis Effects of Mentha arvensis Essential Oil Are Involved in the Inhibition of the NLRP3 Inflammasome in DNCB-Challenged Atopic Dermatitis BALB/c Mice.

The NLRP3 inflammasome is upregulated by various agents, such as nuclear factor-kappa B (NF-κB), lipopolysaccharide (LPS), and adenosine triphosphate (ATP). The NLRP3 inflammasome facilitations the maturation of interleukin (IL)-1ß, a proinflammatory cytokine that is critically involved in the pathogenesis of atopic dermatitis (AD). Although the NLRP3 inflammasome clearly exacerbates AD symptoms such as erythema and pruritus, drugs for AD patients targeting the NLRP3 inflammasome are still lacking. Based on the previous findings that Mentha arvensis essential oil (MAEO) possesses strong anti-inflammatory and anti-AD properties through its inhibition of the ERK/NF-κB signaling pathway, we postulated that MAEO might be capable of modulating the NLRP3 inflammasome in AD. The aim of this research was to investigate whether MAEO affects the inhibition of NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDMs) stimulated with LPS + ATP in vitro and in a murine model displaying AD-like symptoms induced by 2,4-dinitrochlorobenzene (DNCB) in vivo. We found that MAEO inhibited the expression of NLRP3 and caspase-1, leading to the suppression of NLRP3 inflammasome activation and IL-1ß production in BMDMs stimulated with LPS + ATP. In addition, MAEO exhibited efficacy in ameliorating AD symptoms in a murine model induced by DNCB, as indicated by the reduction in dermatitis score, ear thickness, transepidermal water loss (TEWL), epidermal thickness, and immunoglobulin E (IgE) levels. Furthermore, MAEO attenuated the recruitment of NLRP3-expressing macrophages and NLRP3 inflammasome activation in murine dorsal skin lesions induced by DNCB. Overall, we provide evidence for the anti-AD effects of MAEO via inhibition of NLRP3 inflammasome activation.

Dopamine depletion can be predicted by the aperiodic component of subthalamic local field potentials.

Electrophysiological biomarkers reflecting the pathological activities in the basal ganglia are essential to gain an etiological understanding of Parkinson's disease (PD) and develop a method of diagnosing and treating the disease. Previous studies that explored electrophysiological biomarkers in PD have focused mainly on oscillatory or periodic activities such as beta and gamma oscillations. Emerging evidence has suggested that the nonoscillatory, aperiodic component reflects the firing rate and synaptic current changes corresponding to cognitive and pathological states. Nevertheless, it has never been thoroughly examined whether the aperiodic component can be used as a biomarker that reflects pathological activities in the basal ganglia in PD. In this study, we examined the parameters of the aperiodic component in hemiparkinsonian rats and tested its practicality as an electrophysiological biomarker of pathological activity. We found that a set of aperiodic parameters, aperiodic offset and exponent, were significantly decreased by the nigrostriatal lesion. To further prove the usefulness of the parameters as biomarkers, acute levodopa treatment reverted the aperiodic offset. We then compared the aperiodic parameters with a previously established periodic biomarker of PD, beta frequency oscillation. We found a significantly low negative correlation with beta power. We showed that the performance of the machine learning-based prediction of pathological activities in the basal ganglia can be improved by using both beta power and the aperiodic component, which showed a low correlation with each other. We suggest that the aperiodic component will provide a more sensitive measurement to early diagnosis PD and have the potential to use as the feedback parameter for the adaptive deep brain stimulation.

Second-Derivative-Based Background Drift Removal for a Tonic Dopamine Measurement in Fast-Scan Cyclic Voltammetry.

The dysregulation of dopamine, a neuromodulator, is associated with a broad spectrum of brain disorders, including Parkinson's disease, addiction, and schizophrenia. Quantitative measurements of dopamine are essential for understanding dopamine functional dynamics. Fast-scan cyclic voltammetry (FSCV) is the most popular electrochemical technique for measuring real-time in vivo dopamine level changes. Standard FSCV has only analyzed "phasic dopamine" (changes in seconds) because the gradual generation of background charging current is inevitable and is the primary noise source in the low-frequency band. Although "tonic dopamine" (changes in minutes to hours) is critical for understanding the dopamine system, an electrochemical technique capable of simultaneously measuring phasic and tonic dopamine in an in vivo environment has not been established. Several modified voltammetric techniques have been developed for measuring tonic dopamine; however, the sampling rates (0.1-0.05 Hz) are too low to be useful. Further investigation of the in vivo applicability of previously developed background drift removal methods for measuring tonic dopamine levels is required. We developed a second-derivative-based background removal (SDBR) method for simultaneously measuring phasic and tonic neurotransmitter levels in real-time. The performance of this technique was tested via in silico and in vitro tonic dopamine experiments. Furthermore, its applicability was tested in vivo. SDBR is a simple, robust, postprocessing technique that can extract tonic neurotransmitter levels from all FSCV data. As SDBR is calculated in individual-scan voltammogram units, it can be applied to any real-time closed-loop system that uses a neurotransmitter as a biomarker.

Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses.

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.

Potential Therapeutic Approaches through Modulating the Autophagy Process for Skin Barrier Dysfunction.

Autophagy is an attractive process to researchers who are seeking novel potential treatments for various diseases. Autophagy plays a critical role in degrading damaged cellular organelles, supporting normal cell development, and maintaining cellular homeostasis. Because of the various effects of autophagy, recent human genome research has focused on evaluating the relationship between autophagy and a wide variety of diseases, such as autoimmune diseases, cancers, and inflammatory diseases. The skin is the largest organ in the body and provides the first line of defense against environmental hazards, including UV damage, chemical toxins, injuries, oxidative stress, and microorganisms. Autophagy takes part in endogenous defense mechanisms by controlling skin homeostasis. In this manner, regulating autophagy might contribute to the treatment of skin barrier dysfunctions. Various studies are ongoing to elucidate the association between autophagy and skin-related diseases in order to find potential therapeutic approaches. However, little evidence has been gathered about the relationship between autophagy and the skin. In this review, we highlight the previous findings of autophagy and skin barrier disorders and suggest potential therapeutic strategies. The recent research regarding autophagy in acne and skin aging is also discussed.

NLRP3 Inflammasome Activation Is Involved in LPA1-Mediated Brain Injury after Transient Focal Cerebral Ischemia.

Lysophosphatidic acid receptor 1 (LPA1) contributes to brain injury following transient focal cerebral ischemia. However, the mechanism remains unclear. Here, we investigated whether nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation might be an underlying mechanism involved in the pathogenesis of brain injury associated with LPA1 following ischemic challenge with transient middle cerebral artery occlusion (tMCAO). Suppressing LPA1 activity by its antagonist attenuated NLRP3 upregulation in the penumbra and ischemic core regions, particularly in ionized calcium-binding adapter molecule 1 (Iba1)-expressing cells like macrophages of mouse after tMCAO challenge. It also suppressed NLRP3 inflammasome activation, such as caspase-1 activation, interleukin 1ß (IL-1ß) maturation, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, in a post-ischemic brain. The role of LPA1 in NLRP3 inflammasome activation was confirmed in vitro using lipopolysaccharide-primed bone marrow-derived macrophages, followed by LPA exposure. Suppressing LPA1 activity by either pharmacological antagonism or genetic knockdown attenuated NLRP3 upregulation, caspase-1 activation, IL-1ß maturation, and IL-1ß secretion in these cells. Furthermore, nuclear factor-κB (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 were found to be LPA1-dependent effector pathways in these cells. Collectively, results of the current study first demonstrate that LPA1 could contribute to ischemic brain injury by activating NLRP3 inflammasome with underlying effector mechanisms.

REDD1 Is Involved in Amyloid ß-Induced Synaptic Dysfunction and Memory Impairment.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.

Lysophosphatidic acid receptor 1 (LPA1) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia.

BACKGROUND: Lysophosphatidic acid receptor 1 (LPA1) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA1 might also be a therapeutic strategy for cerebral ischemia because LPA1 triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO). METHODS: To address the role of LPA1 in the ischemic brain damage, we used AM095, a selective LPA1 antagonist, as a pharmacological tool and lentivirus bearing a specific LPA1 shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA1 in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis. RESULTS: AM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1 day after tMCAO, which was reaffirmed by LPA1 shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3 days after tMCAO. LPA1 antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA1 antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-κB activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA1-driven proinflammatory responses appeared to occur in activated microglia because NF-κB activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA1 in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA1 activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA1 influenced PI3K/Akt and MAPKs; suppressing LPA1 activity decreased MAPK activation and increased Akt phosphorylation. CONCLUSION: This study demonstrates that LPA1 is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage.

Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

BACKGROUND: The pathogenic roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling in cerebral ischemia have been evidenced mainly through the efficacy of FTY720 that binds non-selectively to four of the five S1P receptors (S1P1,3,4,5). Recently, S1P1 and S1P2 were identified as specific receptor subtypes that contribute to brain injury in cerebral ischemia; however, the possible involvement of other S1P receptors remains unknown. S1P3 can be the candidate because of its upregulation in the ischemic brain, which was addressed in this study, along with underlying pathogenic mechanisms. METHODS: We used transient middle cerebral artery occlusion/reperfusion (tMCAO), a mouse model of transient focal cerebral ischemia. To identify S1P3 as a pathogenic factor in cerebral ischemia, we employed a specific S1P3 antagonist, CAY10444. Brain damages were assessed by brain infarction, neurological score, and neurodegeneration. Histological assessment was carried out to determine microglial activation, morphological transformation, and proliferation. M1/M2 polarization and relevant signaling pathways were determined by biochemical and immunohistochemical analysis. RESULTS: Inhibiting S1P3 immediately after reperfusion with CAY10444 significantly reduced tMCAO-induced brain infarction, neurological deficit, and neurodegeneration. When S1P3 activity was inhibited, the number of activated microglia was markedly decreased in both the periischemic and ischemic core regions in the ischemic brain 1 and 3 days following tMCAO. Moreover, inhibiting S1P3 significantly restored the microglial shape from amoeboid to ramified microglia in the ischemic core region 3 days after tMCAO, and it attenuated microglial proliferation in the ischemic brain. In addition to these changes, S1P3 signaling influenced the proinflammatory M1 polarization, but not M2. The S1P3-dependent regulation of M1 polarization was clearly shown in activated microglia, which was affirmed by determining the in vivo activation of microglial NF-κB signaling that is responsible for M1 and in vitro expression levels of proinflammatory cytokines in activated microglia. As downstream effector pathways in an ischemic brain, S1P3 influenced phosphorylation of ERK1/2, p38 MAPK, and Akt. CONCLUSIONS: This study identified S1P3 as a pathogenic mediator in an ischemic brain along with underlying mechanisms, involving its modulation of microglial activation and M1 polarization, further suggesting that S1P3 can be a therapeutic target for cerebral ischemia.

Structural and biochemical insights into the role of testis-expressed gene 14 (TEX14) in forming the stable intercellular bridges of germ cells.

Intercellular bridges are a conserved feature of spermatogenesis in mammalian germ cells and derive from arresting cell abscission at the final stage of cytokinesis. However, it remains to be fully understood how germ cell abscission is arrested in the presence of general cytokinesis components. The TEX14 (testis-expressed gene 14) protein is recruited to the midbody and plays a key role in the inactivation of germ cell abscission. To gain insights into the structural organization of TEX14 at the midbody, we have determined the crystal structures of the EABR [endosomal sorting complex required for transport (ESCRT) and ALIX-binding region] of CEP55 bound to the TEX14 peptide (or its chimeric peptides) and performed functional characterization of the CEP55-TEX14 interaction by multiexperiment analyses. We show that TEX14 interacts with CEP55-EABR via its AxGPPx3Y (Ala793, Gly795, Pro796, Pro797, and Tyr801) and PP (Pro803 and Pro804) sequences, which together form the AxGPPx3YxPP motif. TEX14 competitively binds to CEP55-EABR to prevent the recruitment of ALIX, which is a component of the ESCRT machinery with the AxGPPx3Y motif. We also demonstrate that a high affinity and a low dissociation rate of TEX14 to CEP55, and an increase in the local concentration of TEX14, cooperatively prevent ALIX from recruiting ESCRT complexes to the midbody. The action mechanism of TEX14 suggests a scheme of how to inactivate the abscission of abnormal cells, including cancer cells.

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice.

Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice. Increased urinary albumin excretion, increased glomerular tuft area and volume, and mesangial matrix expansion were observed in db/db mice and reduced by treatment with ki16425, a LPA receptor 1/3 antagonist. Transforming growth factor (TGF)ß expression and Smad-2/3 phosphorylation were upregulated in SV40 MES13 cells by LPA stimulation or in the kidney cortex of db/db mice, and this was blocked by ki16425 treatment. LPA receptor 1 siRNA treatment inhibited LPA-induced TGFß expression, whereas cells overexpressing LPA receptor 1 showed enhanced LPA-induced TGFß expression. LPA treatment of SV40 MES13 cells increased phosphorylated glycogen synthase kinase (GSK)3ß at Ser9 and induced translocation of sterol regulatory element-binding protein (SREBP)1 into the nucleus. Blocking GSK3ß phosphorylation inhibited SREBP1 activation and consequently blocked LPA-induced TGFß expression in SV40 MES13 cells. Phosphorylated GSK3ß and nuclear SREBP1 accumulation were increased in the kidney cortex of db/db mice and ki16425 treatment blocked these pathways. Thus, LPA receptor 1 signaling increased TGFß expression via GSK3ß phosphorylation and SREBP1 activation, contributing to the development of diabetic nephropathy.

Retrospective Comparative Analysis of Elbow Arthroscopy Used to Treat Primary Osteoarthritis With and Without Release of the Posterior Band of the Medial Collateral Ligament.

PURPOSE: To evaluate the clinical and functional outcomes of arthroscopic debridement arthroplasty with the release of the posterior band of the medial collateral ligament in patients with primary osteoarthritis. METHODS: We evaluated 43 patients treated with arthroscopic debridement arthroplasty for elbow osteoarthritis from February 2006 to February 2014. In group A (n = 19), the posterior band of the medial collateral ligament was released, and in group B (n = 24), it was not released. The mean follow-up period in groups A and B was 55.4 months (range, 24-100 months) and 62.2 months (range, 24-103 months), respectively. Clinical results were evaluated by measuring the preoperative and postoperative range of motion (ROM) of the elbow, visual analog scale score, and Mayo Elbow Performance Score. RESULTS: Both groups showed significant improvement in clinical outcome (visual analog scale and Mayo Elbow Performance Score) at the final follow-up compared with preoperative evaluation (group A, P = .009 and .013, respectively; group B, P = .015 and .008, respectively). Group A showed significant improvement in increased flexion at 6 months of follow-up (P = .043). However, there was no statistically significant difference in postoperative ROM and clinical results between the 2 groups at the final follow-up (P = .482). CONCLUSIONS: Arthroscopic debridement arthroplasty with the release of the posterior band of the medial collateral ligament was associated with improved flexion at the 6-month postoperative follow-up, but no significant difference between the groups was observed at the final follow-up. Therefore, the additional release of the posterior band of the medial collateral ligament may be unnecessary for improving postoperative ROM. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Pruning-Based Sparse Recovery for Electrocardiogram Reconstruction from Compressed Measurements.

Due to the necessity of the low-power implementation of newly-developed electrocardiogram (ECG) sensors, exact ECG data reconstruction from the compressed measurements has received much attention in recent years. Our interest lies in improving the compression ratio (CR), as well as the ECG reconstruction performance of the sparse signal recovery. To this end, we propose a sparse signal reconstruction method by pruning-based tree search, which attempts to choose the globally-optimal solution by minimizing the cost function. In order to achieve low complexity for the real-time implementation, we employ a novel pruning strategy to avoid exhaustive tree search. Through the restricted isometry property (RIP)-based analysis, we show that the exact recovery condition of our approach is more relaxed than any of the existing methods. Through the simulations, we demonstrate that the proposed approach outperforms the existing sparse recovery methods for ECG reconstruction.

Matrix metalloproteinase-8 plays a pivotal role in neuroinflammation by modulating TNF-α activation.

Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood-brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α-converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the proinflammatory role of microglial MMP-8 was obtained from an in vivo animal model of neuroinflammatory disorder. MMP-8 is upregulated in septic conditions, particularly in microglia. Administration of M8I or MMP-8 short hairpin RNA significantly inhibits microglial activation and expression/secretion of TNF-α in brain tissue, serum, and cerebrospinal fluid of LPS-induced septic mice. These results demonstrate that MMP-8 critically mediates microglial activation by modulating TNF-α activity, which may explain neuroinflammation in septic mouse brain.

Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement.

Electroencephalograms (EEGs) measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI) studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR) is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP) signal that represents a brain's response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE) schemes based on a joint maximum likelihood (ML) criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°.

Proteinase 3 Induces Neuronal Cell Death Through Microglial Activation.

Proteinase 3 (PR3) is released from neutrophil granules and is involved in the inflammatory process. PR3 is implicated in antimicrobial defense and cell death, but the exact role of PR3 in the brain is less defined. Microglia is the major immune effector cells in the CNS and is activated by brain injury. In the present study, the effect of PR3 on glial activation was investigated. Microglial activation was assessed by the intracellular level of reactive oxygen species and expression of inflammatory cytokines. The conditioned media from activated microglia by PR3 was used for measuring the neurotoxic effects of PR3-stimulated microglia. The effects of PR3 in vivo were measured by microinjecting PR3 into the rat brain. Herein we show that PR3 increased the inflammatory responses including the intracellular ROS and pro-inflammatory cytokine production in rat primary microglia. Conditioned media from PR3-treated microglia induced neuronal cell death in a concentration dependent manner. Furthermore, microinjected PR3 into the striatum of the rat brain induced microglial activation and neuronal cell death. Interestingly treatment with anti-PR3 monoclonal antibody and protease inhibitors ameliorated microglial activation induced by PR3 in primary microglia and striatum, which also prevented neuronal cell death in both conditions. The data presented here suggest that PR3 is a direct modulator of microglial activation and causes neuronal death through the augmentation of inflammatory responses. We suggest that PR3 could be a new modulator of neuroinflammation, and blocking PR3 would be a promising novel therapeutic target for neuroinflammatory disease such as stroke and Alzheimer's disease.

Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-α. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.