Fetal Electrocardiogram Extraction from the Mother's Abdominal Signal Using the Ensemble Kalman Filter.

Fetal electrocardiogram (fECG) assessment is essential throughout pregnancy to monitor the wellbeing and development of the fetus, and to possibly diagnose potential congenital heart defects. Due to the high noise incorporated in the abdominal ECG (aECG) signals, the extraction of fECG has been challenging. And it is even a lot more difficult for fECG extraction if only one channel of aECG is provided, i.e., in a compact patch device. In this paper, we propose a novel algorithm based on the Ensemble Kalman filter (EnKF) for non-invasive fECG extraction from a single-channel aECG signal. To assess the performance of the proposed algorithm, we used our own clinical data, obtained from a pilot study with 10 subjects each of 20 min recording, and data from the PhysioNet 2013 Challenge bank with labeled QRS complex annotations. The proposed methodology shows the average positive predictive value (PPV) of 97.59%, sensitivity (SE) of 96.91%, and F1-score of 97.25% from the PhysioNet 2013 Challenge bank. Our results also indicate that the proposed algorithm is reliable and effective, and it outperforms the recently proposed extended Kalman filter (EKF) based algorithm.

An Efficient and Robust Deep Learning Method with 1-D Octave Convolution to Extract Fetal Electrocardiogram.

The invasive method of fetal electrocardiogram (fECG) monitoring is widely used with electrodes directly attached to the fetal scalp. There are potential risks such as infection and, thus, it is usually carried out during labor in rare cases. Recent advances in electronics and technologies have enabled fECG monitoring from the early stages of pregnancy through fECG extraction from the combined fetal/maternal ECG (f/mECG) signal recorded non-invasively in the abdominal area of the mother. However, cumbersome algorithms that require the reference maternal ECG as well as heavy feature crafting makes out-of-clinics fECG monitoring in daily life not yet feasible. To address these challenges, we proposed a pure end-to-end deep learning model to detect fetal QRS complexes (i.e., the main spikes observed on a fetal ECG waveform). Additionally, the model has the residual network (ResNet) architecture that adopts the novel 1-D octave convolution (OctConv) for learning multiple temporal frequency features, which in turn reduce memory and computational cost. Importantly, the model is capable of highlighting the contribution of regions that are more prominent for the detection. To evaluate our approach, data from the PhysioNet 2013 Challenge with labeled QRS complex annotations were used in the original form, and the data were then modified with Gaussian and motion noise, mimicking real-world scenarios. The model can achieve a F1 score of 91.1% while being able to save more than 50% computing cost with less than 2% performance degradation, demonstrating the effectiveness of our method.

Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy.

Adult zebrafish is an emerging vertebrate model for studying genetic basis of cardiomyopathies; but whether the simple fish heart can model essential features of hypertrophic cardiomyopathy (HCM) remained unknown. Here, we report a comprehensive phenotyping of a lamp2 knockout (KO) mutant. LAMP2 encodes a lysosomal protein and is a causative gene of Danon disease that is characterized by HCM and massive autophagic vacuoles accumulation in the tissues. There is no effective therapy yet to treat this most lethal cardiomyopathy in the young. First, we did find the autophagic vacuoles accumulation in cardiac tissues from lamp2 KO. Next, through employing a set of emerging phenotyping tools, we revealed heart failure phenotypes in the lamp2 KO mutants, including decreased ventricular ejection fraction, reduced physical exercise capacity, blunted ß-adrenergic contractile response, and enlarged atrium. We also noted changes of the following indices suggesting cardiac hypertrophic remodeling in lamp2 KO: a rounded heart shape, increased end-systolic ventricular volume and density of ventricular myocardium, elevated actomyosin activation kinetics together with increased maximal isometric tension at the level of cardiac myofibrils. Lastly, we assessed the function of lysosomal-localized mTOR on the lamp2-associated Danon disease. We found that haploinsufficiency of mtor was able to normalize some characteristics of the lamp2 KO, including ejection fraction, ß-adrenergic response, and the actomyosin activation kinetics. In summary, we demonstrate the feasibility of modeling the inherited HCM in the adult zebrafish, which can be used to develop potential therapies.

Acquisition, Processing and Analysis of Electrocardiogram in Awake Zebrafish.

Long-term monitoring of intrinsic electrocardiogram (ECG) in zebrafish plays a crucial role in heart disease studies as well as drug screening. In this work, we developed a polymer-based apparatus with embedded flexible thin-film electrodes to acquire ECG signals of awake zebrafish. The apparatus was made of polydimethylsiloxane (PDMS) using the molding technique with molds formed by 3D printing. A graphical user interface (GUI) was built in National Instruments LabView platform for real-time recording, processing and analysis. The program provided important features, such as signal de-noising, characteristic wave detection and anomaly detection. Further, it could operate on both real-time coming signals as well as previously-saved data, facilitating analysis and interpretation. We demonstrated the use of our system to investigate the effects of the anesthetic drug, namely Tricaine (MS-222), on cardiac electrophysiology of zebrafish, revealing promising findings. We speculate that our novel system may contribute to a host of studies in various disciplines using the zebrafish model.

[Application and analysis of ethnic medicines in "Three Minorities" in Inner Mongolia].

This paper investigates and counts the ethnic medicines of the Ewenki,Daur and Oroqen ethnic groups,which are known as the " Three Minorities" in Inner Mongolia. Through the methods of literature collection,interview investigation,and resource investigation,different ethnic medicines were collected on the main diseases,drug varieties,drug-injection sites,and drug administration methods. Through data statistics and SPSS analysis,the similarities and individual differences between the three ethnic groups were clarified. The results indicated the predicament of the current national medicine,which is helpful for the protection and inheritance of ethnic medicine.

[Status analysis and strategic thinking on Mongolian medicine standardization].

Standardization is the progress of human civilization. It is also an important technical system for normalizing economy and social development and a basic element in the core competitive power of a country. This paper emphasized on the importance of accelerating the standardization of Mongolian medicine for international development of national medicine and improving the international competitiveness. Summed up the Mongolian medicine standardization work achieved the stage results. Achievements on Mongolian medicine standardization were summarized and the existed problems were also analyzed. Such as, imperfect Mongolian medicine standard system and operation mechanism, the lack of application and personnel of Mongolian medicine. Corresponding measures, such as improving the Mongolian medicine standardization system and its support system construction; establishing personnel long-term training mechanism; the establishment of Mongolian medicine standard implementation-promotion-evaluation-feedback mechanism and other corresponding measures, were also provide.

Real-Time Monitoring and Analysis of Zebrafish Electrocardiogram with Anomaly Detection.

Heart disease is the leading cause of mortality in the U.S. with approximately 610,000 people dying every year. Effective therapies for many cardiac diseases are lacking, largely due to an incomplete understanding of their genetic basis and underlying molecular mechanisms. Zebrafish (Danio rerio) are an excellent model system for studying heart disease as they enable a forward genetic approach to tackle this unmet medical need. In recent years, our team has been employing electrocardiogram (ECG) as an efficient tool to study the zebrafish heart along with conventional approaches, such as immunohistochemistry, DNA and protein analyses. We have overcome various challenges in the small size and aquatic environment of zebrafish in order to obtain ECG signals with favorable signal-to-noise ratio (SNR), and high spatial and temporal resolution. In this paper, we highlight our recent efforts in zebrafish ECG acquisition with a cost-effective simplified microelectrode array (MEA) membrane providing multi-channel recording, a novel multi-chamber apparatus for simultaneous screening, and a LabVIEW program to facilitate recording and processing. We also demonstrate the use of machine learning-based programs to recognize specific ECG patterns, yielding promising results with our current limited amount of zebrafish data. Our solutions hold promise to carry out numerous studies of heart diseases, drug screening, stem cell-based therapy validation, and regenerative medicine.

Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain.

Patients with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic liver disease) commonly develop debilitating symptoms (i.e., sickness behaviors) that arise from changes in brain function. The microbiota-gut-brain axis alters brain function and probiotic ingestion can influence behavior. However, how probiotics do this remains unclear. We have previously described a novel periphery-to-brain communication pathway in the setting of peripheral organ inflammation whereby monocytes are recruited to the brain in response to systemic TNF-α signaling, leading to microglial activation and subsequently driving sickness behavior development. Therefore, we investigated whether probiotic ingestion (i.e., probiotic mixture VSL#3) alters this periphery-to-brain communication pathway, thereby reducing subsequent sickness behavior development. Using a well characterized mouse model of liver inflammation, we now show that probiotic (VSL#3) treatment attenuates sickness behavior development in mice with liver inflammation without affecting disease severity, gut microbiota composition, or gut permeability. Attenuation of sickness behavior development was associated with reductions in microglial activation and cerebral monocyte infiltration. These events were paralleled by changes in markers of systemic immune activation, including decreased circulating TNF-α levels. Our observations highlight a novel pathway through which probiotics mediate cerebral changes and alter behavior. These findings allow for the potential development of novel therapeutic interventions targeted at the gut microbiome to treat inflammation-associated sickness behaviors in patients with systemic inflammatory diseases. SIGNIFICANCE STATEMENT: This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life.

[Ecology suitability study of Cistanche deserticola in Alxa].

The distribution information of Cistanche deserticola was collected by interview investigation and field survey, and 55 related environmental factors were collected, the habitat suitability study was conducted based on geographic information system (GIS) and Maximum entropy model. The AUCs of ROC curve were both above 0.9, indicating that the predictive results with the maxent model were highly precise. The results showed that 14 major environmental factors have obvious influence on ecology suitability distributions of C. deserticola, including vegetation type et al, the suitable distribution areas are mainly concentrated in the central of Alxa Youqi, the north of Alxa Zouqi and the south-east of Ejin Banner, including Tamusu towns, Alateng towns et al, The zoning results basically coincide with the genuine producing areas, and further afford new suitable distribution areas, which can provide reference for the siting of introduction and cultivation of C. deserticola.

P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.

Sickness behaviors, such as fatigue, mood alterations, and cognitive dysfunction, which result from changes in central neurotransmission, are prevalent in systemic inflammatory diseases and greatly impact patient quality of life. Although, microglia (resident cerebral immune cells) and cytokines (e.g., TNFα) are associated with changes in central neurotransmission, the link between peripheral organ inflammation, circulating cytokine signaling, and microglial activation remains poorly understood. Here we demonstrate, using cerebral intravital microscopy, that in response to liver inflammation, there is increased monocyte specific rolling and adhesion along cerebral endothelial cells (CECs). Peripheral TNFα-TNFR1 signaling and the adhesion molecule P-selectin are central mediators of these monocyte-CEC adhesive interactions which were found to be closely associated with microglial activation, decreased central neural excitability and sickness behavior development. Similar monocyte-CEC adhesive interactions were also observed in another mouse model of peripheral organ inflammation (i.e., 2,4-dinitrobenzene sulfonic acid-induced colitis). Our observations provide a clear link between peripheral organ inflammation and cerebral changes that impact behavior, which can potentially allow for novel therapeutic interventions in patients with systemic inflammatory diseases.

Consecutive treatments of methamphetamine promote the development of cardiac pathological symptoms in zebrafish.

Chronic methamphetamine use, a widespread drug epidemic, has been associated with cardiac morphological and electrical remodeling, leading to the development of numerous cardiovascular diseases. While methamphetamine has been documented to induce arrhythmia, most results originate from clinical trials from users who experienced different durations of methamphetamine abuse, providing no documentation on the use of methamphetamine in standardized settings. Additionally, the underlying molecular mechanism on how methamphetamine affects the cardiovascular system remains elusive. A relationship was sought between cardiotoxicity and arrhythmia with associated methamphetamine abuse in zebrafish to identify and to understand the adverse cardiac symptoms associated with methamphetamine. Zebrafish were first treated with methamphetamine 3 times a week over a 2-week duration. Immediately after treatment, zebrafish underwent electrocardiogram (ECG) measurement using an in-house developed acquisition system for electrophysiological analysis. Subsequent analyses of cAMP expression and Ca2+ regulation in zebrafish cardiomyocytes were conducted. cAMP is vital to development of myocardial fibrosis and arrhythmia, prominent symptoms in the development of cardiovascular diseases. Ca2+ dysregulation is also a factor in inducing arrhythmias. During the first week of treatment, zebrafish that were administered with methamphetamine displayed a decrease in heart rate, which persisted throughout the second week and remained significantly lower than the heart rate of untreated fish. Results also indicate an increased heart rate variability during the early stage of treatment followed by a decrease in the late stage for methamphetamine-treated fish over the duration of the experiment, suggesting a biphasic response to methamphetamine exposure. Methamphetamine-treated fish also exhibited reduced QTc intervals throughout the experiment. Results from the cAMP and Ca2+ assays demonstrate that cAMP was upregulated and Ca2+ was dysregulated in response to methamphetamine treatment. Collagenic assays indicated significant fibrotic response to methamphetamine treatment. These results provide potential insight into the role of methamphetamine in the development of fibrosis and arrhythmia due to downstream effectors of cAMP.

Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice.

BACKGROUND & AIMS: Cholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (T(regs)) can suppress inflammation; however, a role for T(regs) in modulating sickness behaviours has not been evaluated. METHODS: A mouse model of cholestatic liver injury due to bile duct ligation (BDL) was used to study the role of T(regs) in sickness behaviour development. RESULTS: BDL mice developed reproducible sickness behaviours, as assessed in a social investigation paradigm, characterized by decreased social investigative behaviour and increased immobility. Depletion of peripheral T(regs) in BDL mice worsened BDL-associated sickness behaviours, whereas infusion of T(regs) improved these behaviours; however, liver injury severity was not altered by T(reg) manipulation. Hepatic IL-6 mRNA and circulating IL-6 levels were elevated in BDL vs. control mice, and were elevated further in T(reg)-depleted BDL mice, but were decreased after infusion of T(regs) in BDL mice. IL-6 knock out (KO) BDL mice exhibited a marked reduction in sickness behaviours, compared to wildtype BDL mice. Furthermore, IL-6 KO BDL mice injected with rmIL-6 displayed sickness behaviours similar to wildtype BDL mice, whereas saline injection did not alter behaviour in IL-6 KO BDL mice. BDL was associated with increased hippocampal cerebral endothelial cell p-STAT3 expression, which was significantly reduced in IL-6 KO BDL mice. CONCLUSIONS: T(regs) modulate sickness behaviour development in the setting of cholestatic liver injury, driven mainly through T(reg) inhibition of circulating monocyte and hepatic IL-6 production, and subsequent signalling via circulating IL-6 acting at the level of the cerebral endothelium.

Lullaby: A Novel Algorithm to Extract Fetal QRS in Real Time Using Periodic Trend Feature.

Fetal heart rate (fHR) is an important indicator for monitoring of fetal cardiac health and development. The widely-used method based on ultrasound, however, is not continuous and often requires an expert to perform; thus, it is mostly used in clinics during checkups. The advances in wearable technology have paved the way for home assessment of fHR via the extraction of the mother's abdominal electrocardiogram (ECG) acquired by novel patches. Several methods have been developed for such; however, the computation is either too slow for real-time monitoring or too heavy to be performed in a wearable. In this work, we develop and validate the Lullaby algorithm - a novel method for fetal QRS extraction from aECG. The results showed that Lullaby is almost 7 times faster than existing methods with a better F1-score of 0.815, holding promise to transform perinatal monitoring.

Microelectrode array membranes to simultaneously assess cardiac and neurological signals of xenopus laevis under chemical exposures and environmental changes.

Simultaneous monitoring of electrocardiogram (ECG) and electroencephalogram (EEG) in studied animal models requires innovative engineering techniques that can capture minute physiological changes. However, this is often administered with a bulky and/or invasive system that may cause discomfort to animals and signal distortions. Here, we develop an integrated bioelectronic sensing system to provide simultaneous recordings of ECG and EEG in real-time for Xenopus laevis. The microelectrode array (MEA) membrane and the distinct anatomy of Xenopus offer noninvasive multi-modal electrophysiological monitoring with favorable spatial resolution. The system was validated under different environmental conditions, including drug exposure and temperature changes. Under the exposure of Pentylenetetrazol (PTZ), an epilepsy-inducing drug, clear ECG and EEG alterations, including frequent ictal and interictal EEG events, 30 dB average EEG amplitude elevations, abnormal ECG morphology, and heart rate changes, were observed. Furthermore, the ECG and EEG were monitored and analyzed under different temperatures. A decrease in relative power of delta band was observed when cold environment was brought about, in contrast to an increase in relative power of other higher frequency bands while the ECG remained stable. Overall, the real-time electrophysiology monitoring system using the Xenopus model holds potential for many applications in drug screening and remote environmental monitoring.

A novel wireless ECG system for prolonged monitoring of multiple zebrafish for heart disease and drug screening studies.

Zebrafish and their mutant lines have been extensively used in cardiovascular studies. In the current study, the novel system, Zebra II, is presented for prolonged electrocardiogram (ECG) acquisition and analysis for multiple zebrafish within controllable working environments. The Zebra II is composed of a perfusion system, apparatuses, sensors, and an in-house electronic system. First, the Zebra II is validated in comparison with a benchmark system, namely iWORX, through various experiments. The validation displayed comparable results in terms of data quality and ECG changes in response to drug treatment. The effects of anesthetic drugs and temperature variation on zebrafish ECG were subsequently investigated in experiments that need real-time data assessment. The Zebra II's capability of continuous anesthetic administration enabled prolonged ECG acquisition up to 1 h compared to that of 5 min in existing systems. The novel, cloud-based, automated analysis with data obtained from four fish further provided a useful solution for combinatorial experiments and helped save significant time and effort. The system showed robust ECG acquisition and analytics for various applications including arrhythmia in sodium induced sinus arrest, temperature-induced heart rate variation, and drug-induced arrhythmia in Tg(SCN5A-D1275N) mutant and wildtype fish. The multiple channel acquisition also enabled the implementation of randomized controlled trials on zebrafish models. The developed ECG system holds promise and solves current drawbacks in order to greatly accelerate drug screening applications and other cardiovascular studies using zebrafish.

A phenotype-based forward genetic screen identifies Dnajb6 as a sick sinus syndrome gene.

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (Danio rerio) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart's primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411, in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.

Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis.

NKT cells are highly enriched within the liver. On activation NKT cells rapidly release large quantities of different cytokines which subsequently activate, recruit, or modulate cells important for the development of hepatic inflammation. Recently, it has been demonstrated that NKT cells can also produce interleukin-17 (IL-17), a proinflammatory cytokine that is also known to have diverse immunoregulatory effects. The role played by IL-17 in hepatic inflammation is unclear. Here we show that during α-galactosylceramide (αGalCer)-induced hepatitis in mice, a model of hepatitis driven by specific activation of the innate immune system via NKT cells within the liver, NK1.1+ and CD4+ iNKT cells rapidly produce IL-17 and are the main IL-17-producing cells within the liver. Administration of IL-17 neutralizing monoclonal antibodies before αGalCer injection significantly exacerbated hepatitis, in association with a significant increase in hepatic neutrophil and proinflammatory monocyte (ie, producing IL-12, tumor necrosis factor-α) recruitment, and increased hepatic mRNA and protein expression for the relevant neutrophil and monocyte chemokines CXCL5/LIX and CCL2/MCP-1, respectively. In contrast, administration of exogenous recombinant murine IL-17 before α-GalCer injection ameliorated hepatitis and inhibited the recruitment of inflammatory monocytes into the liver. Our results demonstrate that hepatic iNKT cells specifically activated with α-GalCer rapidly produce IL-17, and IL-17 produced after α-GalCer administration inhibits the development of hepatitis.

Development of a Home-based Fetal Electrocardiogram (ECG) Monitoring System.

We develop a novel wearable fetal electrocardiogram (fECG) monitoring system consisting of an abdominal patch that communicates with a smart device. The system has two main components: the fetal patch and the monitoring app. The fetal patch has electronics and recording electrodes fabricated on a hybrid flexible-rigid platform while the Android app is developed for a wide range of applications. The patch collects the abdominal ECG (aECG) signals that are sent to the smart device app via secure Bluetooth Low Energy (BLE) communication. The app software connects to a cloud server where processing and extraction algorithms are executed for real-time fECG extraction and fetal heartrate (fHR) calculation from the collected raw data. We have validated the algorithms and real-time data recordings on pregnant subjects yielding promising results. Our system has the potential to transform the currently used fetal monitoring system to an effective distanced and telematernity care.

NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway.

Esophageal squamous cell carcinoma (ESCC) causes aggressive and lethal malignancies with extremely poor prognoses, and accounts for about 90% of cases of esophageal cancer. Neuropilin and tolloid-like 2 (NETO2) protein coding genes have been associated with various human cancers. Nevertheless, little information is reported about the phenotypic expression and its clinical significance in ESCC progression. Here, our study found that NETO2 expression in ESCC patients was associated with tumor clinical stage and lymph node metastasis status. Gain-of-function and loss-of-function analyses showed that NETO2 stimulated ESCC cell proliferation while suppressing apoptosis in vitro and enhanced tumor growth in vivo. Moreover, knockdown of NETO2 significantly inhibited migration and invasion in combination with regulation of epithelial-mesenchymal transition (EMT) related markers. Mechanistically, overexpression of NETO2 increased the phosphorylation of ERK, PI3k/AKT, and Nuclear factor erythroid-2-related factor 2(Nrf2), whereas silencing NETO2 decreased the phosphorylation of these targets. Our data suggest that Nrf2 was a critical downstream event responsible for triggering the PI3K/AKT and ERK signaling pathways and plays a crucial role in NETO2-mediated tumorigenesis. Taken together, NETO2 acts as an oncogene and might serve as a novel therapeutic target or prognostic biomarker in ESCC patients.

Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation.

In inflammatory diseases occurring outside the CNS, communication between the periphery and the brain via humoral and/or neural routes results in central neural changes and associated behavioral alterations. We have recently identified another immune-to-CNS communication pathway in the setting of organ-centered peripheral inflammation: namely, the entrance of immune cells into the brain. In our current study, using a mouse model of inflammatory liver injury, we have confirmed the significant infiltration of activated monocytes into the brain in mice with hepatic inflammation and have defined the mechanism that mediates this trafficking of monocytes. Specifically, we show that in the presence of hepatic inflammation, mice demonstrate elevated cerebral monocyte chemoattractant protein (MCP)-1 levels, as well as increased numbers of circulating CCR2-expressing monocytes. Cerebral recruitment of monocytes was abolished in inflamed mice that lacked MCP-1/CCL2 or CCR2. Furthermore, in mice with hepatic inflammation, microglia were activated and produced MCP-1/CCL2 before cerebral monocyte infiltration. Moreover, peripheral tumor necrosis factor (TNF)alpha signaling was required to stimulate microglia to produce MCP-1/CCL2. TNFalpha signaling via TNF receptor 1 (TNFR1) is required for these observed effects since in TNFR1 deficient mice with hepatic inflammation, microglial expression of MCP-1/CCL2 and cerebral monocyte recruitment were both markedly inhibited, whereas there was no inhibition in TNFR2 deficient mice. Our results identify the existence of a novel immune-to-CNS communication pathway occurring in the setting of peripheral organ-centered inflammation which may have specific implications for the development of alterations in cerebral neurotransmission commonly encountered in numerous inflammatory diseases occurring outside the CNS.