The immunometabolic landscape of bone marrow cells in multiple sclerosis.

In multiple sclerosis (MS), the bone marrow hematopoietic system supplies immune cells to orchestrate central nervous system (CNS) inflammation and autoimmunity. Understanding the metabolic processes within the bone marrow is essential for unraveling the phenotype and function of immune cells. However, a comprehensive exploration of the metabolic landscape and its association with systemic immune response in MS at the single-cell level has yet to be elucidated. Herein, we conducted an analysis of 70 289 bone marrow cells obtained from seven patients with MS and seven health controls (referenced as HRA001783) to address this question. Our focus was primarily on investigating the metabolic preferences of diverse immune cell populations and delineating their metabolic manifestations in the bone marrow microenvironment of MS. Through our analysis, we observed the activation of carbohydrate and amino acid metabolic pathways in the bone marrow cells of MS patients. Notably, we discovered significant metabolic alterations in cell-cell communication within the plasma cell population in the MS bone marrow. These findings shed light on the complex metabolic landscape within the bone marrow niche during MS and highlight the distinctive metabolic characteristics of plasma cells in this context, which may provoke novel understanding of MS pathogenesis and promote future design of immune therapies.

Performance Enhancement of INS and UWB Fusion Positioning Method Based on Two-Level Error Model.

In GNSS-denied environments, especially when losing measurement sensor data, inertial navigation system (INS) accuracy is critical to the precise positioning of vehicles, and an accurate INS error compensation model is the most effective way to improve INS accuracy. To this end, a two-level error model is proposed, which comprehensively utilizes the mechanism error model and propagation error model. Based on this model, the INS and ultra-wideband (UWB) fusion positioning method is derived relying on the extended Kalman filter (EKF) method. To further improve accuracy, the data prefiltering algorithm of the wavelet shrinkage method based on Stein's unbiased risk estimate-Shrink (SURE-Shrink) threshold is summarized for raw inertial measurement unit (IMU) data. The experimental results show that by employing the SURE-Shrink wavelet denoising method, positioning accuracy is improved by 76.6%; by applying the two-level error model, the accuracy is further improved by 84.3%. More importantly, at the point when the vehicle motion state changes, adopting the two-level error model can provide higher computational stability and less fluctuation in trajectory curves.

IMU/UWB Fusion Method Using a Complementary Filter and a Kalman Filter for Hybrid Upper Limb Motion Estimation.

Motion capture systems have enormously benefited the research into human-computer interaction in the aerospace field. Given the high cost and susceptibility to lighting conditions of optical motion capture systems, as well as considering the drift in IMU sensors, this paper utilizes a fusion approach with low-cost wearable sensors for hybrid upper limb motion tracking. We propose a novel algorithm that combines the fourth-order Runge-Kutta (RK4) Madgwick complementary orientation filter and the Kalman filter for motion estimation through the data fusion of an inertial measurement unit (IMU) and an ultrawideband (UWB). The Madgwick RK4 orientation filter is used to compensate gyroscope drift through the optimal fusion of a magnetic, angular rate, and gravity (MARG) system, without requiring knowledge of noise distribution for implementation. Then, considering the error distribution provided by the UWB system, we employ a Kalman filter to estimate and fuse the UWB measurements to further reduce the drift error. Adopting the cube distribution of four anchors, the drift-free position obtained by the UWB localization Kalman filter is used to fuse the position calculated by IMU. The proposed algorithm has been tested by various movements and has demonstrated an average decrease in the RMSE of 1.2 cm from the IMU method to IMU/UWB fusion method. The experimental results represent the high feasibility and stability of our proposed algorithm for accurately tracking the movements of human upper limbs.

How does UV-B stress affect secondary metabolites of Scutellaria baicalensis in vitro shoots grown at different 6-benzyl aminopurine concentrations?

Ultraviolet-B (UV-B) radiation is one of the abiotic stresses that can significantly affect the secondary metabolite accumulation in in vitro tissue cultures of medicinal plants. The present study investigated the effects of UV-B radiation on the secondary metabolites and antioxidant activities of Scutellaria baicalensis in vitro shoots grown at different concentrations of 6-benzyl aminopurine (6-BA), which is the cytokinin most widely used in plant tissue culture. The UV-B radiation caused significant increases in lipid peroxidation, total phenolic, and flavonoid contents, and antioxidant activities in the in vitro shoots grown at lower 6-BA concentrations (0 and 1 mg L-1 ), while it did not cause any significant changes in those grown at higher 6-BA concentrations (2 and 3 mg L-1 ). However, the UV-B radiation significantly altered the contents of main individual flavonoids at both lower and higher 6-BA concentrations. Upon UV-B radiation, aglycones (including baicalein, wogonin, and scutellarein) increased, while glucuronides such as baicalin and wogonoside decreased; this was more evident at higher 6-BA concentrations. This study demonstrated that the effects of UV-B radiation on the secondary metabolites of S. baicalensis in vitro shoots highly depended on the 6-BA concentration in the culture medium.

In vitro production of atractylon and ß-eudesmol from Atractylodes chinensis by adventitious root culture.

Atractylodes chinensis is a medicinal plant widely used for the treatment of gastric disorders, and its main bioactive compounds are atractylon and ß-eudesmol. This study was purposed to establish the adventitious root culture system of A. chinensis for in vitro production of atractylon and ß-eudesmol. The main parameters in the adventitious root induction and suspension cultures were optimized to maximize the culture efficiency. Adventitious roots were induced most efficiently from leaf explants on Murashige and Skoog (MS) solid medium containing 1.5 mg/L naphthaleneacetic acid (NAA) and 30 g/L sucrose with the highest root induction rate of approximately 92% and 12.9 roots per explant. During the adventitious root suspension culture, the root biomass and the accumulated content of the target compounds simultaneously increased to reach the maximum values after 8 weeks of culture. The maximum yield of the target compounds (total concentration 3.38 mg/g DW, total yield 2.66 mg) was achieved in the roots cultured in ½ MS liquid medium supplemented with 2.0 mg/L IBA, 3.2 mg/L NAA, and 40 g/L sucrose with the inoculum density of 8 g/L. Through the central composite design experiment, it was found that the combined use of different types of auxins in the suspension culture could further improve root growth and metabolite accumulation than the application of only one type of auxin. This work provides a new possibility to have a promising candidate for the industrial production of A. chinensis pharmaceuticals without relying on wild resources or field cultivation. KEY POINTS: • The induction culture was optimized for efficient root induction. • Suspension culture was optimized for the atractylon and ß-eudesmol production. • Combined use of different auxins improves root growth and metabolite accumulation.

User Authentication Method Based on Keystroke Dynamics and Mouse Dynamics with Scene-Irrelated Features in Hybrid Scenes.

In order to improve user authentication accuracy based on keystroke dynamics and mouse dynamics in hybrid scenes and to consider the user operation changes in different scenes that aggravate user status changes and make it difficult to simulate user behaviors, we present a user authentication method entitled SIURUA. SIURUA uses scene-irrelated features and user-related features for user identification. First, features are extracted based on keystroke data and mouse movement data. Next, scene-irrelated features that have a low correlation with scenes are obtained. Finally, scene-irrelated features are fused with user-related features to ensure the integrity of the features. Experimental results show that the proposed method has the advantage of improving user authentication accuracy in hybrid scenes, with an accuracy of 84% obtained in the experiment.

Six New Diterpene Glycosides from the Soft Coral Lemnaliabournei.

A chemical study on the extracts of soft coral Lemnalia bournei resulted in the isolation and identification of six new bicyclic diterpene glycosides including three new lemnaboursides E-G (1-3), and three new lemnadiolboursides A-C (4-6), along with three known lemnaboursides (7-9). Their structures were elucidated by detailed spectroscopic analysis, ECD analysis, chemical methods, and comparison with the literature data. Lemnadiolboursides A-C (4-6) contained a lemnal-1(10)-ene-7,12-diol moiety compared with the lemnaboursides. All these compounds were evaluated for antibacterial activity; cell growth inhibition of A549, Hela, HepG2, and CCRF-CEM cancer cell lines; and inhibition of LPS-induced NO production in RAW264.7 macrophages. The results indicated that compounds 1, 2, and 4-6 exhibited antibacterial activity against Staphylococcus aureus and Bacillus subtilis (MIC 4-16 µg/mL); compounds 1-9 displayed low cytotoxicity on the CCRF-CEM cell lines (IC50 10.44-27.40 µM); and compounds 1, 2, and 5 showed weak inhibition against LPS-induced NO production (IC50 21.56-28.06 µM).

Comparative Metabolomics Reveals Fungal Conversion of Co-Existing Bacterial Metabolites within a Synthetic Aspergillus-Streptomyces Community.

In nature, secondary metabolites have been proven to be the essential communication media between co-occurring microorganisms and to influence their relationship with each other. In this study, we conducted a metabolomics survey of the secondary metabolites of an artificial co-culture related to a hydrothermal vent fungal-bacterial community comprising Aspergillus sclerotiorum and Streptomyces and their reciprocal relationship. The fungal strain was found to increase the secretion of notoamides and the compound cyclo(Pro-Trp) produced by the actinomycetes strain was discovered to be the responsible molecule. This led to the hypothesis that the fungi transformed cyclo(Pro-Trp) synthesized by the actinomycetes as the biosynthetic precursors of notoamides in the chemical communication. Further analysis showed Streptomyces sp. WU20 was efficient in transforming amino acids into cyclo(Pro-Trp) and adding tryptophan as well as proline into the chemical communication enhanced the induction of the notoamide accumulation. Thus, we propose that the microbial transformation during the synthetic metabolically-mediated chemical communication might be a promising means of speeding up the discovery of novel bioactive molecules. The objective of this research was to clarify the mechanism of microbial transformation for the chemical communication. Besides, this research also highlights the utility of mass spectrometry-based metabolomics as an effective tool in the direct biochemical analysis of community metabolites.

Personality Classification of Social Users Based on Feature Fusion.

Based on the openness and accessibility of user data, personality recognition is widely used in personalized recommendation, intelligent medicine, natural language processing, and so on. Existing approaches usually adopt a single deep learning mechanism to extract personality information from user data, which leads to semantic loss to some extent. In addition, researchers encode scattered user posts in a sequential or hierarchical manner, ignoring the connection between posts and the unequal value of different posts to classification tasks. We propose a hierarchical hybrid model based on a self-attention mechanism, namely HMAttn-ECBiL, to fully excavate deep semantic information horizontally and vertically. Multiple modules composed of convolutional neural network and bi-directional long short-term memory encode different types of personality representations in a hierarchical and partitioned manner, which pays attention to the contribution of different words in posts and different posts to personality information and captures the dependencies between scattered posts. Moreover, the addition of a word embedding module effectively makes up for the original semantics filtered by a deep neural network. We verified the hybrid model on the MyPersonality dataset. The experimental results showed that the classification performance of the hybrid model exceeds the different model architectures and baseline models, and the average accuracy reached 72.01%.

Nanoscale vacuum channel transistor with in-plane collection structure.

High quality nanoscale vacuum channel transistors (NVCTs) enable carriers to transport ballistically through the vacuum nanogap, achieving high speed and frequency characteristic which are essential for on-chip vacuum electronic devices. However, the studies to date have been largely confined to explore the common electrical performance, while the fast response characteristic of NVCTs remains a challenge. We report the fabrication of metal-based NVCT, with sub-100 nm vacuum channel and specific designed in-plane collection structure which can enhance the emission or collection efficiency of the electrons simultaneously. Importantly, the demonstration of a rise/fall time of less than 100 ns is achieved, which is compatible with those high-quality solid-state transistors based on low-dimensional materials. Moreover, the device can also retain excellent electrical performance, exhibiting a high drive current (>10 µA), low work voltage (<10 V) and high on/off current ratio (>104). The verification of fast temporal response of NVCT makes a significant step towards on-chip vacuum electronics with high speed and integration.

Three New Diketopiperazines from the Previously Uncultivable Marine Bacterium Gallaecimonas mangrovi HK-28 Cultivated by iChip.

The in situ application of iChip cultivation in mangrove sediment from Hainan province, China, led to the isolation of a novel bacterial species Gallaecimonas mangrovi HK-28. The extract of G. mangrovi HK-28 exhibited antibiotic activity against the aquatic pathogen Vibrio harveyi, and its chemical constituents were further investigated by bioactivity-guided isolation. Three new diketopiperazines, gallaecimonamides A-C, were accordingly isolated from the AcOEt extract of the fermentation broth of G. mangrovi HK-28. The planar structures of gallaecimonamides A-C were determined using HR-ESI-MS together with 1D- and 2D-NMR. The absolute configurations of gallaecimonamides A-C were assigned by optical rotation, NOESY experiment and TDDFT ECD calculations. The in vitro antibacterial and antimalarial activities of gallaecimonamides A-C were assessed. Gallaecimonamide A was found to display antibacterial activity against V. harveyi with a MIC value of 50 µm. However, gallaecimonamides B and C showed no antibacterial activity against V. harveyi (MIC >300 µm). In addition, all the isolates did not exhibit any inhibitory activities against V. parahaemolyticus (MIC>300 µm) and Plasmodium falciparum W2 (EC50 >100 µg/mL).

Comparative metabolomics reveals defence-related modification of citrinin by Penicillium citrinum within a synthetic Penicillium-Pseudomonas community.

Co-occurring microorganisms have been proved to influence the performance of each other by metabolic means in nature. Here we generated a synthetic fungal-bacterial community comprising Penicillium citrinum and Pseudomonas aeruginosa employing the previously described membrane-separated co-culture device. By applying a newly designed molecular networking routine, new citrinin-related metabolites induced by the fungal-bacterial cross-talk were unveiled in trace amounts. A mechanically cycled co-culture setup with external pumping forces accelerating the chemically interspecies communication was then developed to boost the production of cross-talk-induced metabolites. Multivariate data analysis combined with molecular networking revealed the accumulation of a pair of co-culture-induced molecules whose productions were positively correlated to the exchange rate in the new co-cultures, facilitating the discovery of the previously undescribed antibiotic citrinolide with a novel skeleton. This highly oxidized citrinin adduct showed significantly enhanced antibiotic property against the partner strain P. aeruginosa than its precursor citrinin, suggesting a role in the microbial competition. Thus, we propose competitive-advantage-oriented structural modification driven by microbial defence response mechanism in the interspecies cross-talk might be a promising approach in the search for novel antibiotics. Besides, this study highlights the utility of MS-based metabolomics as an effective tool in the direct biochemical analysis of the community metabolism.

In Vivo Two-Way Redox Cycling System for Independent Duplexed Electrochemical Signal Amplification.

An in vivo two-way redox cycling system based on whole-cell bidirectional electron transfer was developed and applied for independent duplexed electrochemical signal amplification. This duplexed signal amplification system was established by activating the bacterial "inwards" electron transfer at low electrode potential for oxidative cycling, while accomplishing the bacterial "outwards" electron transfer at high electrode potential for reductive cycling. Therefore, with this two-way bioredox cycling system, simultaneous and independent amplification of the electrochemical signals for oxidation and reduction was achieved. More impressively, by using this duplexed signal amplification system, ultrasensitive and simultaneous detection of two different warfare toxins of Pseudomonas aeruginosa was achieved (sensitivity was improved 302 and 579 times, respectively), which makes it possible for double-checking early diagnosis of the P. aeruginosa infections.

Stress-Driven Discovery of New Angucycline-Type Antibiotics from a Marine Streptomyces pratensis NA-ZhouS1.

Natural products from marine actinomycetes remain an important resource for drug discovery, many of which are produced by the genus, Streptomyces. However, in standard laboratory conditions, specific gene clusters in microbes have long been considered silent or covert. Thus, various stress techniques activated latent gene clusters leading to isolation of potential metabolites. This study focused on the analysis of two new angucycline antibiotics isolated from the culture filtrate of a marine Streptomyces pratensis strain NA-ZhouS1, named, stremycin A (1) and B (2) which were further determined based on spectroscopic techniques such as high resolution time of flight mass spectrometry (HR-TOF-MS), 1D, and 2D nuclear magnetic resonance (NMR) experiments. In addition, four other known compounds, namely, 2-[2-(3,5-dimethyl-2-oxo-cyclohexyl)-6-oxo-tetrahydro-pyran-4yl]-acetamide (3), cyclo[l-(4-hydroxyprolinyl)-l-leucine] (4), 2-methyl-3H-quinazoline-4-one (5), and menthane derivative, 3-(hydroxymethyl)-6-isopropyl-10,12-dioxatricyclo[7.2.1.0]dodec-4-en-8-one (6) were obtained and elucidated by means of 1D NMR spectrometry. Herein, we describe the "Metal Stress Technique" applied in the discovery of angucyclines, a distinctive class of antibiotics that are commonly encoded in microbiomes but have never been reported in "Metal Stress" based discovery efforts. Novel antibiotics 1 and 2 exhibited antimicrobial activities against Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus (MRSA), Klebsiella pneumonia, and Escherichia coli with equal minimum inhibitory concentration (MIC) values of 16 µg/mL, while these antibiotics showed inhibition against Bacillus subtilis at MIC value of approximately 8⁻16 µg/mL, respectively. As a result, the outcome of this investigation revealed that metal stress is an effective technique in unlocking the biosynthetic potential and resulting production of novel antibiotics.

Synthetic multispecies microbial communities reveals shifts in secondary metabolism and facilitates cryptic natural product discovery.

Chemically mediated interactions have been hypothesized to be essential for ecosystem functioning as co-occurring organisms can influence the performance of each other by metabolic means. Here, we present a co-culture device that allows co-culturing of microorganisms that are physically separated but can exchange chemical signals and metabolites. This setup was adopted to perform investigations on the secondary metabolisms of both a fungal-bacterial community and an actinomycetic-actinomycetic community. This study employed a metabolomics approach integrating LC-MS profiling, multivariate data analysis and molecular networking techniques. LC-MS measurements revealed a pronounced influence of such chemical communication on the metabolic profiles of synthetic co-culture communities with a group of molecules being induced or upregulated in co-cultures. A novel antibiotic exhibiting antibiotic properties against Klebsiella pneumoniae was unveiled in the fungal-bacterial community. Besides, a further survey of the fungal-bacterial cross-talk indicated that the production of co-culture-induced diphenyl ethers by fungi might result from the fungal response against the secretion of surfactins by bacteria in the cross-talk. This study demonstrated that the presented co-culture device and the metabolomic routine would facilitate the investigation on chemically mediated interactions in nature as well as cryptic natural products discovery.

New compounds from a hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4.

Three new quinazoline derivatives (1-3), one new oxepin-containing natural product (4) and four new cyclopenin derivatives (5-7 and 9) have been isolated from an EtOAc extract of the Taiwan Kueishantao hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. Their planar structures were established by HRMS, 1D and 2D NMR spectroscopic data analyses. The absolute configurations for compounds 1 and 4 were determined by chiral phase HPLC analysis of their hydrolysis products. The absolute configurations of 2, 3 and 7 were defined mainly by comparison of the quantum chemical TDDFT calculated and the experimental ECD spectra, and the absolute configuration of 5 was deduced from comparison of the optical rotation values reported in the literature. The presence of two atropisomers of 5 was established by NOE analyses. The Ile & Val units in compounds 1-3 allowed the assignment of a new quinazoline skeleton and it's the first time the configuration of isoleucine in the quinazoline skeleton was defined. A series of 7-methoxy cyclopenin derivatives were reported for the first time in this study. The bioevaluation of compounds 5, 7, 8 and 9 revealed inhibitory activities against E. coli at MIC values around 32 µg mL-1.

Stress-driven discovery of a cryptic antibiotic produced by Streptomyces sp. WU20 from Kueishantao hydrothermal vent with an integrated metabolomics strategy.

Marine hydrothermal microorganisms respond rapidly to the changes in the concentrations and availability of metals within hydrothermal vent microbial habitats which are strongly influenced by elevated levels of heavy metals. Most hydrothermal vent actinomycetes possess a remarkable capability for the synthesis of a broad variety of biologically active secondary metabolites. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known compounds. Here, we report the identification of a novel antibiotic produced by Streptomyces sp. WU20 isolated from the metal-rich hydrothermal vents in Taiwan Kueishantao, following a strategy based on metal induction of silent genes combined with metabolomics analytical methods. HPLC-guided isolation by tracking the target peak resulted in the characterization of the novel compound 1 with antimicrobial activity against Bacillus subtilis. The stress metabolite 1 induced by nickel is structurally totally different compared with the normally produced compounds. This study underlines the applicability of metal induction combined with metabolic analytical techniques in accelerating the exploration of novel antibiotics and other medically relevant natural products.

Production of an antibiotic enterocin from a marine actinobacteria strain H1003 by metal-stress technique with enhanced enrichment using response surface methodology.

Elicitation by chemical means including heavy metals is one of a new technique for drug discoveries. In this research, the effect of heavy metals on marine actinobacteria Streptomyces sp. H-1003 for the production of enterocin, with a strong broad spectrum activity, along optimized fermented medium was firstly investigated. The optimum metal stress conditions consisted of culturing marine actinobacteria strain H-1003 with addition of cobalt ions at 2mM in optimized Gause's medium having starch at 20mg/L for 10 days at 180 revolution/min. Under these conditions, enterocin production was enhanced with a value of 5.33mg/L, which was totally absent at the normal culture of strain H-1003 and much higher than other tested metal-stress conditions. This work triumphantly announced a prodigious effect of heavy metals on marine actinobacteria with fringe benefits as a key tool of enterocin production.

An Unusual Conformational Isomer of Verrucosidin Backbone from a Hydrothermal Vent Fungus, Penicillium sp. Y-50-10.

A new verrucosidin derivative, methyl isoverrucosidinol (1), was isolated from the marine fungus Penicillium sp. Y-50-10, dwelling in sulfur rich sediment in the Kueishantao hydrothermal vents off Taiwan. The structure was established by spectroscopic means including HRMS and 2D-NMR spectroscopic analysis. The absolute configuration was defined mainly by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Among hitherto known compounds with a verrucosidine backbone isolated from natural resource, compound 1 represents the first example of a new conformational isomer of its skeleton, exhibiting antibiotic activity against Bacillus subtilis with MIC value 32 µg/mL.

Exploring Determinants of Successful Weight Loss with the Use of a Smartphone Healthcare Application: Secondary Analysis of a Randomized Clinical Trial.

Dietary and physical activity interventions through smartphone healthcare applications (apps) have recently surged in popularity as effective methods for weight loss. However, the specific factors contributing to successful weight loss remain uncertain. We conducted an analysis of baseline characteristics and app usage frequencies over three months among 68 Japanese adults with overweight and obesity who were assigned to the intervention group in a previous randomized controlled trial. Logistic regression analysis revealed a negative association (OR: 0.248; p = 0.018) between having a walking habit at baseline and successful weight loss, defined as a 3% reduction in initial weight. Additionally, slower walking speeds and family medical history were identified as potential predictors of successful weight loss. These findings offer insights into the profile of individuals who achieve success in weight loss through our smartphone app, providing valuable guidance for the development of future healthcare apps.