Machine learning guided prediction of warfarin blood levels for personalized medicine based on clinical longitudinal data from cardiac surgery patients: a prospective observational study.

BACKGROUND: Warfarin is a common oral anticoagulant, and its effects vary widely among individuals. Numerous dose-prediction algorithms have been reported based on cross-sectional data generated via multiple linear regression or machine learning. This study aimed to construct an information fusion perturbation theory and machine learning prediction model of warfarin blood levels based on clinical longitudinal data from cardiac surgery patients. METHODS AND MATERIAL: The data of 246 patients were obtained from electronic medical records. Continuous variables were processed by calculating the distance of the raw data with the moving average (MA ∆vki(sj)), and categorical variables in different attribute groups were processed using Euclidean distance (ED ǁ∆vk(sj)ǁ). Regression and classification analyses were performed on the raw data, MA ∆vki(sj), and ED ǁ∆vk(sj)ǁ. Different machine-learning algorithms were chosen for the STATISTICA and WEKA software. RESULTS: The random forest (RF) algorithm was the best for predicting continuous outputs using the raw data. The correlation coefficients of the RF algorithm were 0.978 and 0.595 for the training and validation sets, respectively, and the mean absolute errors were 0.135 and 0.362 for the training and validation sets, respectively. The proportion of ideal predictions of the RF algorithm was 59.0%. General discriminant analysis (GDA) was the best algorithm for predicting the categorical outputs using the MA ∆vki(sj) data. The GDA algorithm's total true positive rate (TPR) was 95.4% and 95.6% for the training and validation sets, respectively, with MA ∆vki(sj) data. CONCLUSIONS: An information fusion perturbation theory and machine learning model for predicting warfarin blood levels was established. A model based on the RF algorithm could be used to predict the target international normalized ratio (INR), and a model based on the GDA algorithm could be used to predict the probability of being within the target INR range under different clinical scenarios.

Multi-frequency signal acquisition and phase measurement in space gravitational wave detection.

To enhance the accuracy of phase measurement and to prevent tracking errors, it is crucial to effectively read the multi-frequency signal in space gravitational wave detection. In this paper, a novel signal acquisition method called the multi-frequency acquisition algorithm is proposed and implemented. Different from the traditional single-frequency acquisition, the signal characteristics of amplitude and frequency are both considered to better distinguish different frequency components. A phasemeter integrated with the acquisition method and narrow-bandwidth digital phase-locked loop is constructed for the method test and verification. The results show that the multi-frequency acquisition unit can capture all the frequencies of an input signal in several milliseconds. The precision is better than ±200 Hz under a low SNR (signal-to-noise ratio) of 0 dB. The phase noise can reach 2 µrad/Hz1/2 in the frequency range of 0.1-1 Hz and satisfy the requirement of the space gravitational wave detection in all frequency ranges.

Liquid crystal monomers disrupt photoreceptor patterning of zebrafish larvae via thyroid hormone signaling.

Liquid crystal monomers (LCMs) are the raw material for liquid crystal displays, and their use is steadily increasing in electronic products. Recently, LCMs have been reported to be novel endocrine disrupting chemicals, however, the mechanisms underlying their potential for thyroid hormone disruption and visual toxicity are not well understood. In this study, six widely used fluorinated LCMs (FLCMs) were selected to determine putative mechanisms underlying FLCM-induced toxicity to the zebrafish thyroid and visual systems. Exposure to FLCMs caused damage to retinal structures and reduced cell density of ganglion cell layer, inner nuclear layer, and photoreceptor layer approximately 12.6-46.1%. Exposure to FLCMs also disrupted thyroid hormone levels and perturbed the hypothalamic-pituitary-thyroid axis by affecting key enzymes and protein in zebrafish larvae. A thyroid hormone-dependent GH3 cell viability assay supported the hypothesis that FLCMs act as thyroid hormone disrupting chemicals. It was also determined that FLCMs containing aliphatic ring structures may have a higher potential for T3 antagonism compared to FLCMs without an aliphatic ring. Molecular docking in silico suggested that FLCMs may affect biological functions of thyroxine binding globulin, membrane receptor integrin, and thyroid receptor beta. Lastly, the visual motor response of zebrafish in red- and green-light was significantly inhibited following exposure to FLCMs. Taken together, we demonstrate that FLCMs can act as thyroid hormone disruptors to induce visual dysfunction in zebrafish via several molecular mechanisms.

Genomic Analysis of Kitasatospora setae to Explore Its Biosynthetic Potential Regarding Secondary Metabolites.

Actinomycetes have long been recognized as important sources of clinical antibiotics. However, the exploration of rare actinomycetes, despite their potential for producing bioactive molecules, has remained relatively limited compared to the extensively studied Streptomyces genus. The extensive investigation of Streptomyces species and their natural products has led to a diminished probability of discovering novel bioactive compounds from this group. Consequently, our research focus has shifted towards less explored actinomycetes, beyond Streptomyces, with particular emphasis on Kitasatospora setae (K. setae). The genome of K. setae was annotated and analyzed through whole-genome sequencing using multiple bio-informatics tools, revealing an 8.6 Mbp genome with a 74.42% G + C content. AntiSMASH analysis identified 40 putative biosynthetic gene clusters (BGCs), approximately half of which were recessive and unknown. Additionally, metabolomic mining utilizing mass spectrometry demonstrated the potential for this rare actinomycete to generate numerous bioactive compounds such as glycosides and macrolides, with bafilomycin being the major compound produced. Collectively, genomics- and metabolomics-based techniques confirmed K. setae's potential as a bioactive secondary metabolite producer that is worthy of further exploration.

Preparation and chromatographic evaluation of 9-oxa-10-phosphophenanthrene 10-oxide bonded phenyl stationary phase and investigation of its retention mechanism through nuclear magnetic resonance spectroscopy.

BACKGROUND: In reversed-phase liquid chromatography, the C18 alkyl bonded phase, as the primary stationary phase, is widely used in pharmaceutical and food analysis. The phenyl bonded phase often serves as a complementary choice to the C18 phase to enhance the separation performance of specific categories of compounds. However, both C18 and the currently available phenyl bonded phase chromatography columns show room for further optimization in improving the separation efficiency of specific compound classes, such as dihydroflavonoids. Additionally, the potential role and impact of introducing phosphorus groups into chromatographic stationary phases have not been fully explored, indicating a promising direction for research. RESULTS: In the present work, we prepared a novel phenyl stationary phase by bonding 9-oxa-10-phosphaphenanthrene 10-oxide onto silica gel. The obtained material was characterized by scanning electron microscopy, fourier transforms infrared spectroscopy, and elemental analysis. The results show that 9-oxa-10-phosphaphenanthrene 10-oxide was successfully bonded on the silica surface with a load of 3.90 %. Further chromatographic characterization in high-performance liquid chromatography exhibited high column efficiency (40,792 plates m-1 for the determination of biphenyl) and good stability (RSD of 0.28 %∼5.38 %). Moreover, we made a detailed study of the column separation mechanism by nuclear magnetic resonance spectroscopy titration experiment. Comparing to commercial phenyl column, the proposed stationary phase showed shorter retention time and higher throughput. In addition, the stationary phase has a strong ability to separate multiple types of compounds, which provides a new strategy for the separation of complex samples, such as active ingredients in traditional Chinese medicine. SIGNIFICANCE: We have developed a novel phenyl column and conducted a comprehensive examination of its chromatographic performance, demonstrating excellent separation capabilities and high efficiency for both nonpolar and moderately polar aromatic compounds. Additionally, we explored the impact of phosphorus-containing groups on the separation performance of chromatographic stationary phases.

Scalable Customization of Crystallographic Plane Controllable Lithium Metal Anodes for Ultralong-Lasting Lithium Metal Batteries.

A formidable challenge to achieve the practical applications of rechargeable lithium (Li) metal batteries (RLMBs) is to suppress the uncontrollable growth of Li dendrites. One of the most effective solutions is to fabricate Li metal anodes with specific crystal plane, but still lack of a simple and high-efficient approach. Herein, a facile and controllable way for the scalable customization of polished Li metal anodes with highly preferred (110) and (200) crystallographic orientation (donating as polished Li(110) and polished Li(200), respectively) by regulating the times of accumulative roll bonding, is reported. According to the inherent characteristics of polished Li(110)/Li(200), the influence of Li atomic structure on the electrochemical performance of RLMBs is deeply elucidated by combining theoretical calculations with relative experimental proofs. In particular, a polished Li(110) crystal plane is demonstrated to induce Li+ uniform deposition, promoting the formation of flat and dense Li deposits. Impressively, the polished Li(110)||LiFePO4 full cells exhibit unprecedented cycling stability with 10 000 cycles at 10 C almost without capacity degradation, indicating the great potential application prospect of such textured Li metal. More valuably, this work provides an important reference for low-cost, continued, and large-scale production of Li metal anodes with highly preferred crystal orientation through roll-to-roll manufacturability.

A Biomimetic Visual Detection Model: Event-Driven LGMDs Implemented With Fractional Spiking Neuron Circuits.

OBJECTIVE: As biological wide-field visual neurons in locusts, lobula giant motion detectors (LGMDs) can effectively predict collisions and trigger avoidance before the collision occurs. This capability has extensive potential applications in autonomous driving, unmanned aerial vehicles, and more. Currently, describing the LGMD characteristics is divided into two viewpoints, one emphasizing the presynaptic visual pathway and the other emphasizing the postsynaptic LGMDs neuron. Indeed, both have their research support leading to the emergence of two computational models, but both lack a biophysical description of the behavior in the individual LGMD neuron. This paper aims to mimic and explain LGMD's behavior based on fractional spiking neurons and construct a biomimetic visual model for the LGMD compatible with these two characteristics. METHODS: We implement the visual model in the form of spikes by choosing an event camera rather than a conventional CMOS camera to simulate the photoreceptors and follow the topology of the ON/OFF visual pathway, enabling it to incorporate the lateral inhibition to mimic the LGMD's system from the bottom up. Second, most computational models of motion perception use only the dendrites within the LGMD neurons as the ideal pathway for linear summation, ignoring dendritic effects inducing neuronal properties. Thus, we introduced fractional spiking neuron (FSN) circuits into the model by altering dendritic morphological parameters to simulate multi-scale spike frequency adaptation (SFA) observed in LGMDs. In addition, we have attempted to add one more circuit of dendritic trees into fractional spiking neurons to be compatible with the postsynaptic FFI in LGMDs and provide a novel explanatory approach and a predictive model for studying LGMD neurons. RESULTS: Finally, we test that the event-driven biomimetic visual model can achieve collision detection and looming selection in different complex scenes, especially fast-moving objects.

Deficiency of UCHL1 results in insufficient decidualization accompanied by impaired dNK modulation and eventually miscarriage.

BACKGROUND: Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown. METHODS: With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome. RESULTS: The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-ß which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome. CONCLUSIONS: UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.

On the additive artificial intelligence-based discovery of nanoparticle neurodegenerative disease drug delivery systems.

Neurodegenerative diseases are characterized by slowly progressing neuronal cell death. Conventional drug treatment strategies often fail because of poor solubility, low bioavailability, and the inability of the drugs to effectively cross the blood-brain barrier. Therefore, the development of new neurodegenerative disease drugs (NDDs) requires immediate attention. Nanoparticle (NP) systems are of increasing interest for transporting NDDs to the central nervous system. However, discovering effective nanoparticle neuronal disease drug delivery systems (N2D3Ss) is challenging because of the vast number of combinations of NP and NDD compounds, as well as the various assays involved. Artificial intelligence/machine learning (AI/ML) algorithms have the potential to accelerate this process by predicting the most promising NDD and NP candidates for assaying. Nevertheless, the relatively limited amount of reported data on N2D3S activity compared to assayed NDDs makes AI/ML analysis challenging. In this work, the IFPTML technique, which combines information fusion (IF), perturbation theory (PT), and machine learning (ML), was employed to address this challenge. Initially, we conducted the fusion into a unified dataset comprising 4403 NDD assays from ChEMBL and 260 NP cytotoxicity assays from journal articles. Through a resampling process, three new working datasets were generated, each containing 500,000 cases. We utilized linear discriminant analysis (LDA) along with artificial neural network (ANN) algorithms, such as multilayer perceptron (MLP) and deep learning networks (DLN), to construct linear and non-linear IFPTML models. The IFPTML-LDA models exhibited sensitivity (Sn) and specificity (Sp) values in the range of 70% to 73% (>375,000 training cases) and 70% to 80% (>125,000 validation cases), respectively. In contrast, the IFPTML-MLP and IFPTML-DLN achieved Sn and Sp values in the range of 85% to 86% for both training and validation series. Additionally, IFPTML-ANN models showed an area under the receiver operating curve (AUROC) of approximately 0.93 to 0.95. These results indicate that the IFPTML models could serve as valuable tools in the design of drug delivery systems for neurosciences.

Marinicella meishanensis sp. nov., a novel Marinicella member isolated from coastal mudflat sediment of Meishan Islandin the East China Sea.

A Gram-negative, rod-shaped, non-motile and strictly aerobic strain, designated NBU2979T, was isolated from a coastal mudflat located on Meishan Island in the East China Sea. Strain NBU2979T grew optimally at 32 °C, with 2.0 % NaCl (w/v) and at pH 7.0-7.5. The predominant fatty acid (>10 %) was iso-C15 : 0. The major polar lipids included phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, phosphatidyldimethylethanolamine, phosphatidylcholine, an unidentified glycolipid, two unidentified aminophospholipids, an unidentified phospholipid and an unidentified lipid. The only respiratory quinone was ubiquinone-8. Comparative analysis of 16S rRNA gene sequences showed that strain NBU2979T exhibited highest similarity to Marinicella sediminis F2T (98.0 %), Marinicella marina S1101T (97.5 %), Marinicella litoralis KMM 3900T (96.6 %), Marinicella rhabdoformis 3539T (95.5 %), Marinicella pacifica sw153T (95.2 %) and Marinicella gelatinilytica S6413T (94.9 %). Phylogenetic analyses indicated that strain NBU2979T clustered with the genus Marinicella and was closely related to strain M. sediminis F2T. The average nucleotide identity and digital DNA-DNA hybridization values between strain NBU2979T and related species of genus Marinicella were well below the threshold limit for prokaryotic species delineation. The DNA G+C content of strain NBU2979T was 51.6 mol%. Based on its phenotypic, chemotaxonomic and genotypic data, strain NBU2979T (=KCTC 82911T=MCCC 1K06402T) is considered to be a representative of a novel species in the genus Marinicella, for which the name Marinicella meishanensis sp. nov. is proposed.

Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells.

BACKGROUND: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. METHODS: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. RESULTS: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. CONCLUSIONS: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

Elucidating immune-related gene transcriptional programs via factorization of large-scale RNA-profiles.

Recent developments in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy, have encountered challenges such as immune-related adverse events and resistance, especially in solid tumors. To advance the field, a deeper understanding of the molecular mechanisms behind treatment responses and resistance is essential. However, the lack of functionally characterized immune-related gene sets has limited data-driven immunological research. To address this gap, we adopted non-negative matrix factorization on 83 human bulk RNA-seq datasets and constructed 28 immune-specific gene sets. After rigorous immunologist-led manual annotations and orthogonal validations across immunological contexts and functional omics data, we demonstrated that these gene sets can be applied to refine pan-cancer immune subtypes, improve ICB response prediction and functionally annotate spatial transcriptomic data. These functional gene sets, informing diverse immune states, will advance our understanding of immunology and cancer research.

Cyclic peroxides and analogs: Antibacterial, antimalarial, and cytotoxic marine products from Xisha sponge Diacarnus sp.

A chemical investigation of the dichloromethane extract from the Xisha sponge Diacarnus sp. revealed seven undescribed norterpene cyclic peroxides, named diacarperoxides T-Z, and five unreported related norterpenes, named diacarnoids E-I, and eleven previously reported compounds. The structures of these isolated compounds, including their absolute configurations, were elucidated based on extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, Snatzke's method, [Rh2(OCOCF3)4]-induced ECD spectra, and modified Mosher's method. Bioassays were performed to assess the antibacterial activity against six pathogenic bacteria, cytotoxicities toward three cancer cell lines, and antimalarial activity against Plasmodium parasites. Most of the cyclic peroxides exhibited substantial antibacterial activity (MIC 1-8 µg/mL). Diacarperoxide W and nuapapuin A showed substantial antimalarial activity with IC50 values of 0.98 and 2.83 µM. Moreover, many compounds exhibited <50% cell survival rates, and IC50 values of 0.22-6.33 µM. The apoptosis assay showed that nuapapuin A induced cancer cell apoptosis in a dose-dependent manner.

Huang Lian Jie Du Decoction enhances the anti-tumor efficacy of immune checkpoint inhibitors by activating TLR7/8 signalling in melanoma.

BACKGROUND: The clinical application of immune checkpoint inhibitors (ICIs) is limited by their drug resistance, necessitating the development of ICI sensitizers to improve cancer immunotherapy outcomes. Huang Lian Jie Du Decoction (HLJD, Oren-gedoku-to in Japanese, Hwangryunhaedok-tang in Korean), a famous traditional Chinese medicinal prescription, has exhibited potential in the field of cancer treatment. This study aims to investigate the impact of HLJD on the efficacy of ICIs in melanoma and elucidate the underlying mechanisms. METHODS: The potential synergistic effects of HLJD and ICIs were investigated on the tumor-bearing mice model of B16F10 melanoma, and the tumor infiltration of immune cells was tested by flow cytometry. The differential gene expression in tumors between HLJD and ICIs group and ICIs alone group were analyzed by RNA-seq. The effects of HLJD on oxidative stress, TLR7/8, and type I interferons (IFN-Is) signaling were further validated by immunofluorescence, PCR array, and immunochemistry in tumor tissue. RESULTS: HLJD enhanced the anti-tumor effect of ICIs, significantly inhibited tumor growth, and prolonged the survival duration in melanoma. HLJD increased the tumor infiltration of anti-tumor immune cells, especially DCs, CD4+ T cells and CD8+T cells. Mechanically, HLJD activated the oxidative stress and TLR7/8 signaling pathway and IFN-Is-related genes in tumors. CONCLUSIONS: HLJD enhanced the therapeutic benefits of ICIs in melanoma, through increasing reactive oxygen species (ROS), promoting the TLR7/8 pathway, and activating IFN-Is signaling, which in turn activated DCs and T cells.

Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis.

Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

New Diterpenes and Diterpene Glycosides with Antibacterial Activity from Soft Coral Lemnalia bournei.

Five new biflorane-type diterpenoids, biofloranates E-I (1-5), and two new bicyclic diterpene glycosides, lemnaboursides H-I (6-7), along with the known lemnabourside, were isolated from the South China Sea soft coral Lemnalia bournei. Their chemical structures and stereochemistry were determined based on extensive spectroscopic methods, including time-dependent density functional theory (TDDFT) ECD calculations, as well as a comparison of them with the reported values. The antibacterial activities of the isolated compounds were evaluated against five pathogenic bacteria, and all of these diterpenes and diterpene glycosides showed antibacterial activities against Staphylococcus aureus and Bacillus subtilis, with MICs ranging from 4 to 64 µg/mL. In addition, these compounds did not exhibit noticeable cytotoxicities on A549, Hela, and HepG2 cancer cell lines, at 20 µM.

Genetically engineered cell-derived nanovesicles for cancer immunotherapy.

The emergence of immunotherapy has marked a new epoch in cancer treatment, presenting substantial clinical benefits. Extracellular vesicles (EVs), as natural nanocarriers, can deliver biologically active agents in cancer therapy with their inherent biocompatibility and negligible immunogenicity. However, natural EVs have limitations such as inadequate targeting capability, low loading efficacy, and unpredictable side effects. Through progress in genetic engineering, EVs have been modified for enhanced delivery of immunomodulatory agents and antigen presentation with specific cancer targeting ability, deepening the role of EVs in cancer immunotherapy. This review briefly describes typical EV sources, isolation methods, and adjustable targeting of EVs. Furthermore, this review highlights the genetic engineering strategies developed for delivering immunomodulatory agents and antigen presentation in EV-based systems. The prospects and challenges of genetically engineered EVs as cancer immunotherapy in clinical translation are also discussed.

Total ginsenosides decrease Aß production through activating PPARγ.

INTRODUCTION: Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. METHODS: APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aß) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aß production were associated with PPARγ activity. RESULTS: TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aß accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aß1-40 and Aß1-42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. CONCLUSIONS: TG treatment reduced the production of Aß both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aß clearance and ameliorating cognitive deficiency in APP/PS1 mice.

Prognostic influence of weight loss on overweight/obese young heart failure patients.

OBJECTIVES: To explore the prognostic influence of weight loss (WL) on young overweight/obesity (OW/OB) individuals with heart failure (HF). METHODS: Heart failure enrollees (younger than 45 years, body mass index [BMI] of ≥25 kg/m2) who received medical treatment at Beijing Chaoyang Hospital, Beijing, China, were classified into 2 groups according to whether they experienced significant WL (≥5% from baseline one year after discharge). One-year occurrence rate of major adverse cardiac events (MACEs) comprising cardiac death and rehospitalization for HF was determined. RESULTS: Of the 191 individuals recruited for this study, 47 had significant WL. The incidence of ischemic heart disease and obstructive sleep apnea syndrome, as well as BMI and blood pressure, were higher in those with significant WL compared to the control group. Although there was no noteworthy discrepancy in the occurrence of cardiac death between the 2 groups, significant WL correlated independently with a lower incidence of HF re-hospitalization (hazard ratio [HR]=0.32, 95% confidence interval [CI]: [0.11-0.91], p=0.032) and overall MACEs (HR=0.37, 95% CI: [0.14-0.94], p=0.036) in young OW/OB individuals with HF. CONCLUSION: Significant WL may correlate with favorable prognosis in OW/OB young HF patients.

Microfluidic Immunosensing Platform Based on a Rolling Circle Amplification-Assisted DNA Dendrimer Probe for Portable and Sensitive Detection of Allergen-Specific IgE.

The robust point-of-care platform for sensitive, multiplexed, and affordable detection of allergen-specific IgE (sIgE) is an urgent demand in component-resolved diagnostics. Here, we developed a microfluidic immunosensing platform based on a rolling circle amplification-assisted DNA dendrimer probe for sensitive detection of multiple sIgEs. The versatile multichannel microfluidic whole blood analytical device integrates cell filtration, recombinant antigen-modified magnetic enrichment, and DNA dendrimer probe-amplified signal transduction for portable on-chip analysis. Three sIgEs against common oyster allergens were simultaneously detected in blood samples by simple smartphone-based imaging without any pretreatment. The quantitative detection of multiple allergen-specific antibodies on the platform was achieved with limits of detection of less than 50 pg/mL, exhibiting superior sensitivity compared to most point-of-care testing. The detection results of 55 serum samples and 4 whole blood samples were 100% consistent with the ELISA results, confirming the accuracy and stability of our platform. Additionally, the reversible combination of hexahistidine6-tag and Ni-IMAC magbead was elegantly utilized on the immunosensing platform for desired reversibility. With the advantages of general applicability, high sensitivity, and reversibility, the DNA dendrimer-based microfluidic immunosensing platform provides great potential for the portable detection of immune proteins as a point-of-care platform in disease diagnostics and biological analysis.