Single cell atlas of human gastric muscle immune cells and macrophage-driven changes in idiopathic gastroparesis.

Gastrointestinal immune cells, particularly muscularis macrophages (MM) interact with the enteric nervous system and influence gastrointestinal motility. Here we determine the human gastric muscle immunome and its changes in patients with idiopathic gastroparesis (IG). Single cell sequencing was performed on 26,000 CD45+ cells obtained from the gastric tissue of 20 subjects. We demonstrate 11 immune cell clusters with T cells being most abundant followed by myeloid cells. The proportions of cells belonging to the 11 clusters were similar between IG and controls. However, 9/11 clusters showed 578-11,429 differentially expressed genes. In IG, MM had decreased expression of tissue-protective and microglial genes and increased the expression of monocyte trafficking and stromal activating genes. Furthermore, in IG, IL12 mediated JAK-STAT signaling involved in the activation of tissue-resident macrophages and Eph-ephrin signaling involved in monocyte chemotaxis were upregulated. Patients with IG had a greater abundance of monocyte-like cells. These data further link immune dysregulation to the pathophysiology of gastroparesis.

Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.

Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.

Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven-IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.

An autonomous, multi-agent, IoT-empowered space logistics system for mission-critical inventory packing.

In recent aerospace missions, space logistics have proven essential in storing, delivering and returning crew and materials between terrestrial facilities and space stations. Unlike classical commercial logistics, space logistics operations are cost-prohibitive and mission-driven, and its replenishment cycle for essential materials is relatively long. Therefore, the complete utilisation of spacecraft payload is of utmost importance. The theory of the inventory packing problem is extended in this study to build autonomous agents that interact with one another within a space logistics decision support system to reinforce the replenishment decision, chunk loading optimisation, and quality inspection. With the long replenishment cycle time, an agent embedded with interval type-2 fuzzy logic is explored to support chaotic time-series demand forecasting to derive re-order quantities in the desired period. Afterwards, the second agent solves the space chunk loading problem using the differential evolution algorithm to utilise payloads and capacities, particularly cylindrical chunks fully. The third agent measures actual item dimensions and quality to deploy the three-dimensional object scanning devices. Feedback is provided to the second agent to derive optimal chunk-loading instructions. Thanks to the autonomous interactions among the above agents, mission-critical decisions for space logistics are supported to achieve operational excellence.

Blockchain-IoT-Driven Nursing Workforce Planning for Effective Long-Term Care Management in Nursing Homes.

Due to the global ageing population, the increasing demand for long-term care services for the elderly has directed considerable attention towards the renovation of nursing homes. Although nursing homes play an essential role within residential elderly care, professional shortages have created serious pressure on the elderly service sector. Effective workforce planning is vital for improving the efficacy and workload balance of existing nursing staff in today's complex and volatile long-term care service market. Currently, there is lack of an integrated solution to monitor care services and determine the optimal nursing staffing strategy in nursing homes. This study addresses the above challenge through the formulation of nursing staffing optimisation under the blockchain-internet of things (BIoT) environment. Embedding a blockchain into IoT establishes the long-term care platform for the elderly and care workers, thereby decentralising long-term care information in the nursing home network to achieve effective care service monitoring. Moreover, such information is further utilised to optimise nursing staffing by using a genetic algorithm. A case study of a Hong Kong nursing home was conducted to illustrate the effectiveness of the proposed system. We found that the total monthly staffing cost after using the proposed model was significantly lower than the existing practice with a change of -13.48%, which considers the use of heterogeneous workforce and temporary staff. Besides, the care monitoring and staffing flexibility are further enhanced, in which the concept of skill substitution is integrated in nursing staffing optimisation.

Update to the Hong Kong Epilepsy Guideline: evidence-based recommendations for clinical management of women with epilepsy throughout the reproductive cycle.

Since the publication of the Hong Kong Epilepsy Guideline in 2009, there has been significant progress in antiepileptic drug development. New AEDs have emerged, and data about their uses have been published. Women require special attention in epilepsy care. Drug teratogenicity, pregnancy, breastfeeding, contraception, reproduction technology, menopause, and catamenial epilepsy are major topics. Antiepileptic drugs should be chosen individually for patients who are pregnant or may become pregnant with consideration of their teratogenicity and seizure control properties. Folate is commonly prescribed for women of childbearing age who are taking antiepileptic drugs. Spontaneous vaginal delivery and breastfeeding are not contra-indicated in most cases but need to be considered individually based on the patient's medical condition and wishes. Serum drug level monitoring of certain antiepileptic drugs during pregnancy and puerperium can guide dosage adjustment. For catamenial epilepsy, intermittent benzodiazepines such as clobazam during the susceptible phase of the menstrual cycle could be a treatment option.

Long-Term Programming of CD8 T Cell Immunity by Perinatal Exposure to Glucocorticoids.

Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.

A radiation belt of energetic protons located between Saturn and its rings.

Saturn has a sufficiently strong dipole magnetic field to trap high-energy charged particles and form radiation belts, which have been observed outside its rings. Whether stable radiation belts exist near the planet and inward of the rings was previously unknown. The Cassini spacecraft's Magnetosphere Imaging Instrument obtained measurements of a radiation belt that lies just above Saturn's dense atmosphere and is decoupled from the rest of the magnetosphere by the planet's A- to C-rings. The belt extends across the D-ring and comprises protons produced through cosmic ray albedo neutron decay and multiple charge-exchange reactions. These protons are lost to atmospheric neutrals and D-ring dust. Strong proton depletions that map onto features on the D-ring indicate a highly structured and diverse dust environment near Saturn.

Chemical interactions between Saturn's atmosphere and its rings.

The Pioneer and Voyager spacecraft made close-up measurements of Saturn's ionosphere and upper atmosphere in the 1970s and 1980s that suggested a chemical interaction between the rings and atmosphere. Exploring this interaction provides information on ring composition and the influence on Saturn's atmosphere from infalling material. The Cassini Ion Neutral Mass Spectrometer sampled in situ the region between the D ring and Saturn during the spacecraft's Grand Finale phase. We used these measurements to characterize the atmospheric structure and material influx from the rings. The atmospheric He/H2 ratio is 10 to 16%. Volatile compounds from the rings (methane; carbon monoxide and/or molecular nitrogen), as well as larger organic-bearing grains, are flowing inward at a rate of 4800 to 45,000 kilograms per second.

Evaluation of a multiplex flow immunoassay versus conventional assays in detecting autoantibodies in systemic lupus erythematosus.

INTRODUCTION: Conventional diagnostic assays are being replaced with automated multiplex assays, but their performance needs to be evaluated. We compared a multiplex flow immunoassay with conventional techniques in the detection of antinuclear antibodies (ANAs) and antibodies to specific extractable nuclear antigens (ENAs) in serum samples from patients with systemic lupus erythematosus. METHODS: A total of 140 consecutive Chinese patients with systemic lupus erythematosus and 41 healthy controls were included. The automated BioPlex 2200 ANA Screen assay (Bio-Rad Laboratories, Hercules [CA], US) was compared with indirect immunofluorescence. In addition, use of BioPlex 2200 to detect anti-ENA antibodies was compared with in-house assays of countercurrent immunoelectrophoresis (CIEP), enzyme-linked immunosorbent assay (ELISA), and line blot. RESULTS: The sensitivity and specificity of BioPlex in detecting ANAs (91.4% and 95.1%, respectively) were comparable to those of indirect immunofluorescence (90.7% and 85.4%, respectively). Overall, BioPlex achieved the best agreement with ELISA in detecting anti-ENA antibodies: agreement was >90% for most antibody types (κ=0.79-0.94). In contrast, agreement was poorest with CIEP, ranging from 85.6% (κ=0.33) for anti-Sm antibodies to 93.9% (κ=0.88) for anti-Ro antibodies. Overall, BioPlex and ELISA had the highest sensitivity, whereas CIEP had the highest specificity. In terms of disease association, anti-Sm detected by CIEP had the best positive predictive value and specificity for lupus nephritis. CONCLUSIONS: In a local lupus cohort, BioPlex showed comparable sensitivity to indirect immunofluorescence in detecting ANAs and comparable performance to ELISA in detecting anti-ENA antibodies. However, CIEP was the best method in terms of disease specificity.

Prevalence of neutralising antibodies to interferon-beta and clinical response in Chinese patients with relapsing multiple sclerosis.

BACKGROUND: There are no data on neutralising antibodies to interferon-beta and its clinical implications in Chinese patients with multiple sclerosis (MS). OBJECTIVES: The objectives of this study were to investigate the prevalence of neutralising antibodies among Chinese patients with relapsing MS receiving interferon-beta (1a or 1b) and to study the association between neutralising antibodies and the clinical-radiological response. METHODS: We performed a cross-sectional study on MS patients who received interferon-beta for 9 months or more, and evaluated the clinical response by relapses and magnetic resonance imaging lesions. Blood samples were evaluated for myxovirus resistance protein A (MxA) gene expression by polymerase chain reaction, anti-interferon-beta binding antibodies by enzyme-linked immunosorbent assay, and neutralising antibodies by cell-based MxA protein induction and luciferase reporter gene assays. Assay performances were evaluated by receiver operating characteristic analysis. RESULTS: Among 78 subjects recruited, 61/77 (79%) had anti-interferon-beta binding antibodies, and 22/78 (28%) had neutralising antibodies by MxA protein induction assay. The presence of high-titre neutralising antibodies was associated with poor clinical outcome (odds ratio 6.1, 95% confidence interval 1.5-25.6, P = 0.013). The sensitivity and specificity for neutralising antibodies using MxA gene expression assay (cut-off 0.20) was 80% and 68%, respectively (area under the curve 0.71). CONCLUSIONS: Neutralising antibodies are associated with poor clinical outcome in Chinese patients with relapsing MS. MxA gene expression and protein induction assays are complimentary assays for neutralising antibody detection.

Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1ß.

Surface changes on comet 67P/Churyumov-Gerasimenko suggest a more active past.

The Rosetta spacecraft spent ~2 years orbiting comet 67P/Churyumov-Gerasimenko, most of it at distances that allowed surface characterization and monitoring at submeter scales. From December 2014 to June 2016, numerous localized changes were observed, which we attribute to cometary-specific weathering, erosion, and transient events driven by exposure to sunlight and other processes. While the localized changes suggest compositional or physical heterogeneity, their scale has not resulted in substantial alterations to the comet's landscape. This suggests that most of the major landforms were created early in the comet's current orbital configuration. They may even date from earlier if the comet had a larger volatile inventory, particularly of CO or CO2 ices, or contained amorphous ice, which could have triggered activity at greater distances from the Sun.

Seasonal exposure of carbon dioxide ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Carbon dioxide (CO2) is one of the most abundant species in cometary nuclei, but because of its high volatility, CO2 ice is generally only found beneath the surface. We report the infrared spectroscopic identification of a CO2 ice-rich surface area located in the Anhur region of comet 67P/Churyumov-Gerasimenko. Spectral modeling shows that about 0.1% of the 80- by 60-meter area is CO2 ice. This exposed ice was observed a short time after the comet exited local winter; following the increased illumination, the CO2 ice completely disappeared over about 3 weeks. We estimate the mass of the sublimated CO2 ice and the depth of the eroded surface layer. We interpret the presence of CO2 ice as the result of the extreme seasonal changes induced by the rotation and orbit of the comet.

Rosetta's comet 67P/Churyumov-Gerasimenko sheds its dusty mantle to reveal its icy nature.

The Rosetta spacecraft has investigated comet 67P/Churyumov-Gerasimenko from large heliocentric distances to its perihelion passage and beyond. We trace the seasonal and diurnal evolution of the colors of the 67P nucleus, finding changes driven by sublimation and recondensation of water ice. The whole nucleus became relatively bluer near perihelion, as increasing activity removed the surface dust, implying that water ice is widespread underneath the surface. We identified large (1500 square meters) ice-rich patches appearing and then vanishing in about 10 days, indicating small-scale heterogeneities on the nucleus. Thin frosts sublimating in a few minutes are observed close to receding shadows, and rapid variations in color are seen on extended areas close to the terminator. These cyclic processes are widespread and lead to continuously, slightly varying surface properties.

Comparative evaluation of three new commercial immunoassays for anti-Müllerian hormone measurement.

STUDY QUESTION: How do the three new anti-Müllerian hormone (AMH) assay methods, manufactured by Beckman Coulter, Roche and Ansh Labs compare with each other and with the Gen II assay? SUMMARY ANSWER: The three new AMH assays are well correlated among themselves and with the Gen II assay, although differences in calibration do exist. WHAT IS KNOWN ALREADY: The Gen II assay has been the mainstay method for AMH measurement in the past few years. Recently, a few new AMH measurement methods have come to the market. STUDY DESIGN, SIZE, DURATION: This was a prospective assay evaluation performed on 178 human serum samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMH concentration was measured in residual serum samples donated by female patients in a reproductive medicine centre. The three new assay methods were tested in parallel and the numerical values obtained were compared among themselves and with those obtained by the Gen II assay. The assay stability upon different sample storage conditions, intra-assay and inter-assay precision, linearity and dilution recovery, and diagnostic performance for polycystic ovary syndrome (PCOS) of the three new AMH assay methods were also compared. MAIN RESULTS AND THE ROLE OF CHANCE: AMH values measured by the Gen II kit and the three new assay methods have good correlations (R > 0.9 for all pairwise correlations). Values measured by the Ansh Labs assay were significantly higher, whereas those by the Roche assay were significantly lower, than those from the Gen II and Beckman-Coulter automated assays (P < 0.05). AMH values were significantly different when measured on the fresh and frozen-thawed serum sample (at -20oC and -80oC) for all three new methods (P < 0.05), but the magnitude of difference was very small with the Beckman-Coulter automated assay and Roche assay. The intra-assay coefficients of variation (CVs) were 0.7-2.2%, 0.5-1.4%, and 1.4-5.4% for the Beckman-Counter automated, Roche and Ansh Labs assays, respectively. Their inter-assay CVs were 0.9-2.5%, 0.7-1.9%, and 6.2-13.5%, respectively. All three new assay methods showed acceptable linearity, and provided excellent discrimination of PCOS from controls. LIMITATIONS, REASONS FOR CAUTION: The precision and dilution linearity experiments involved a small sample size, although these were not the primary outcome measures and have been properly evaluated in previous publications. The study was not designed or powered for determining diagnostic cut-off values. WIDER IMPLICATIONS OF THE FINDINGS: The results demonstrate that the three new AMH assay methods are all valid methods to be adopted in the field of reproduction and are a basis for further work on their clinical application. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interest to declare. The execution of this study was funded by the Department of Obstetrics and Gynaecology, The University of Hong Kong.