Target Signal Research Articles

Adaptive feature extraction of underwater target signal based on mathematical morphology feature enhancement

This paper proposes an adaptive feature extraction method based on mathematical morphology enhancement to extract effective and stable features under strong ocean noise. Firstly, the traditional mathematical morphology method is improved and a new mathematical morphology filtering method is proposed for feature enhancement of underwater target signals. Secondly, the artificial fish swarm algorithm (AFSA) is improved using weighted power spectral kurtosis (WPSK) to achieve parameter adaptivity. Five measured underwater target signals are used to validate the extracted method, and cosine similarity (CS), signal to noise ratio (SNR), and refined composite multiscale fluctuation dispersion entropy (RCMFDE) are used as evaluation metrics to assess the results and verify the effectiveness of the proposed method. Compared with average filtering (AVGF) and closing opening filtering (COF), the proposed method shows better capability in adaptive feature extraction. Therefore, the proposed mathematical morphological filtering can enhance underwater target features and is very important for adaptive feature extraction of underwater targets.

Signaling Targeting Cost Through List Price

Data analytics enable firms to offer personalized prices to targeted consumers but at a cost. We study a competitive personalized pricing game where the entrant is uncertain about the incumbent’s targeting cost. We demonstrate that implementing personalized pricing through a “list price-discount” scheme allows the incumbent to signal its targeting cost via the list price. This signaling mechanism is effective because the list price serves as a price ceiling, which limits the incumbent’s ability to extract consumer surplus through personalized discounts. The high-cost incumbent can strategically set its list price below the full-information level to separate itself from the low-cost incumbent. Interestingly, the high-cost incumbent prefers separating over pooling only when there is a moderate variation in the incumbents’ targeting costs. Personalized pricing can affect firms differently, benefiting the incumbent but hurting the entrant. Asymmetric information about targeting costs weakens the high-cost incumbent’s incentive to offer personalized discounts, resulting in lower total targeting costs and potentially increasing social surplus. These findings shed light on government regulations and transparency policies regarding personalized pricing. This paper was accepted by Dmitri Kuksov, marketing. Funding: P. Yu was supported by the National Natural Science Foundation of China [Grants 72371038 and 72033003]. J. Zhang was supported by the National Natural Science Foundation of China [Grants 72371061 and 72232001]. Supplemental Material: The online appendices are available at https://doi.org/10.1287/mnsc.2023.02031 .

EPEN-26. DRUG SCREENING IN PATIENT-DERIVED MODELS OF POSTERIOR FOSSA A EPENDYMOMA REVEALS NOVEL PHARMACOLOGICAL VULNERABILITIES

Abstract Ependymoma (EPN) is the third most common malignant intracranial pediatric brain tumor. The most common and aggressive EPN subgroup, posterior fossa ependymoma group A (PFA-EPN), occurs predominantly in younger children and has a 5-year progression free survival of only 33%. Despite progress in the molecular characterization and subtyping of EPN, the standard treatment remains surgery with adjuvant radiation therapy. There is currently no approved role for chemotherapy in PFA-EPN. As such, identifying novel therapies for PFA-EPN is an important unmet medical need. To define therapeutic sensitivities for PFA-EPN, we performed a drug screen on three patient-derived PFA-EPN cell lines. We found that PFA-EPN cell lines were sensitive to several clinically relevant drugs, most notably those targeting epigenetic regulators. This is of a particular interest as a common molecular feature of PFA-EPN is the global reduction of the repressive post-translational histone modification H3K27me3 due to transcriptional EZHIP overexpression or H3 K27M mutations. To further characterize our PFA-EPN cell lines, we performed optical genome mapping analysis, revealing previously undescribed structural variants affecting genes encoding proteins responsible for signaling and transcription. One PFA-EPN sample that showed profound sensitivity to EGFR inhibitors, also had a duplication of a genomic region containing the EGFR ligand encoding genes, AREG, BTC, EREG, and EPGN. We are currently working to validate these results in larger cohorts of PFA-EPN models. Collectively, these findings provide new clues on drugs, signaling and putative therapeutic targets in these rare yet aggressive tumors.

Analysis of the Mechanism of Ophiopogon japonicus in Treating Pneumonia Based on Network Pharmacology

This study explores the mechanism of Ophiopogon japonicus in treating pneumonia through network pharmacology, establishes a physiological and pharmacological relationship between the two based on targets, and emphasizes the interaction between signaling pathways and targets. By utilizing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, specific biological processes and signaling pathways are utilized to enhance the understanding of the medicinal properties of traditional Chinese medicine through the use of bioinformatics and biomedical tools. This method aims to identify the key targets and signaling pathways of Ophiopogon japonicus affecting pneumonia status, providing insights into its anti-inflammatory effect in the lungs. The active application of network pharmacology methods in the field of pneumonia is a new trend in the modernization of traditional Chinese medicine.

The orchestrated feature of Cornus kousa fruit and gut microbiota against obesity via integrated pharmacology

AbstractCornus kousa fruit (CKF) has been utilized as anti‐obesity supplementation in East Asia, including Korea, and gut microbiota (GM) might have synergistic effects on obesity (OB) via its interplay. We aimed to decode molecule(s), mechanism(s), and target(s) on interplay between CKF and GM via network pharmacology analysis. The final targets were analyzed by protein–protein interaction (PPI) networks and a bubble plot. The GM interacted with significant targets identified by the gutMGene database. The relationships among CKF or GM, signaling pathways, targets, and molecules (CGSTM) were plotted by R package. Finally, molecular docking assay and density functional theory (DFT) were performed to validate its affinity. The final targets (22) were selected on OB‐responded targets, indicating that interleukin‐6 (IL6) was the most crucial protein‐coding target on PPI networks. A bubble plot and CGSTM networks suggested that the advanced glycation end‐receptor for advanced glycation end products signaling pathway in diabetic complications is inhibited by CKF and peroxisome proliferator–activated receptor (PPAR) signaling pathway is activated by GM. As the most stable conformers, IL6‐equol complex was attributed to GM, and PPAR alpha‐linoleic acid, PPAR delta‐stearic acid, and fatty acid–binding protein 4‐dimethyl 2,3‐bis(1,3‐dimethylindol‐2‐yl) fumarate complex were attributed to CKF. Noticeably, stearic acid was removed by DFT analysis; all other three molecules were proposed as good electron donators with the higher electronegativity compared with a standard drug (Orlistat). This study shows that integrated pharmacological analysis can enable to decode the unknown relationships between CKF and GM. Overall, this study reveals that the combination of CKF and favorable GM might exert dual therapeutic effects on OB.

Structure and regulatory mechanisms of food‐derived peptides in inflammatory bowel disease: A review

AbstractThe number of patients with inflammatory bowel disease (IBD) is increasing worldwide. Since IBD is a chronic disease that seriously affects patients' life quality, preventing and alleviating IBD with natural and less side effect substances has become a research hotspot. Food‐derived bioactive peptides have been an attractive research focus due to their high efficiency and low toxicity. This paper comprehensively summarizes food‐derived peptides with intestinal health effects, focusing on peptide sequences with IBD‐regulatory effects and emphasizing the effects of their structure and physicochemical properties such as peptide length, amino acid composition, and net charge on their function. We also analyzed its regulatory mechanisms, mainly in 5 aspects: modulating the intestinal microbiota, decreasing intestinal epithelial permeability, increasing antioxidant ability, regulating the expression of inflammatory cytokines, and targeting signaling pathways. This review will help establish novel, efficient screening methods for IBD‐regulatory peptides and contribute to further research and discovery of them.

Auditory Sensory Gating: Effects of Noise.

Cortical auditory evoked potentials (CAEPs) indicate that noise degrades auditory neural encoding, causing decreased peak amplitude and increased peak latency. Different types of noise affect CAEP responses, with greater informational masking causing additional degradation. In noisy conditions, attention can improve target signals' neural encoding, reflected by an increased CAEP amplitude, which may be facilitated through various inhibitory mechanisms at both pre-attentive and attentive levels. While previous research has mainly focused on inhibition effects during attentive auditory processing in noise, the impact of noise on the neural response during the pre-attentive phase remains unclear. Therefore, this preliminary study aimed to assess the auditory gating response, reflective of the sensory inhibitory stage, to repeated vowel pairs presented in background noise. CAEPs were recorded via high-density EEG in fifteen normal-hearing adults in quiet and noise conditions with low and high informational masking. The difference between the average CAEP peak amplitude evoked by each vowel in the pair was compared across conditions. Scalp maps were generated to observe general cortical inhibitory networks in each condition. Significant gating occurred in quiet, while noise conditions resulted in a significantly decreased gating response. The gating function was significantly degraded in noise with less informational masking content, coinciding with a reduced activation of inhibitory gating networks. These findings illustrate the adverse effect of noise on pre-attentive inhibition related to speech perception.

Palindrome sequence mediated target recycling integrating with self-priming assisted signal reaction for sensitive miRNA detection

The development of a sensitive and isothermal technique with a greatly enhanced miRNA detection signal is still technically problematic due to the low abundance of miRNA and high sequence similarities with homologous miRNAs. Herein, we propose a novel fluorescence approach for sensitive and reliable miRNA detection by integrating the palindrome sequence mediated target recycling with self-priming assisted signal reaction. In this method, a dual toehold DNA nano-probe (HT) with two functional arms is designed to mediate specific target recognition and signal amplification. In the presence of target miRNA, it binds to the recognition module of HT probe, releasing the “2” sequence to initiate strand displacement amplification (SDA) and a self-priming-induced signal reaction. Based on the elegant design, the proposed method exhibits a wide linear response range exceeding five orders of magnitude and a low limit of detection of 0.96 fM according to the 3δ rule. The non-specific signal is below 5 % for non-target miRNA detection. Taking the merits of excellent sensitivity, desirable specificity, and superior anti-interference ability, the proposed approach shows a promising prospect for detecting miRNAs in complicated biological environments and early diagnosis of diseases.

Developing Methods for Assessing Mental Activity Using Human-Smartphone Interactions: Comparative Analysis of Activity Levels and Phase Patterns in General Mental Activities, Working Mental Activities, and Physical Activities.

Human biological rhythms are commonly assessed through physical activity (PA) measurement, but mental activity may offer a more substantial reflection of human biological rhythms. This study proposes a novel approach based on human-smartphone interaction to compute mental activity, encompassing general mental activity (GMA) and working mental activity (WMA). A total of 24 health care professionals participated, wearing wrist actigraphy devices and using the "Staff Hours" app for more than 457 person-days, including 332 workdays and 125 nonworkdays. PA was measured using actigraphy, while GMA and WMA were assessed based on patterns of smartphone interactions. To model WMA, machine learning techniques such as extreme gradient boosting and convolutional neural networks were applied, using human-smartphone interaction patterns and GPS-defined work hours. The data were organized by date and divided into person-days, with an 80:20 split for training and testing data sets to minimize overfitting and maximize model robustness. The study also adopted the M10 metric to quantify daily activity levels by calculating the average acceleration during the 10-hour period of highest activity each day, which facilitated the assessment of the interrelations between PA, GMA, and WMA and sleep indicators. Phase differences, such as those between PA and GMA, were defined using a second-order Butterworth filter and Hilbert transform to extract and calculate circadian rhythms and instantaneous phases. This calculation involved subtracting the phase of the reference signal from that of the target signal and averaging these differences to provide a stable and clear measure of the phase relationship between the signals. Additionally, multilevel modeling explored associations between sleep indicators (total sleep time, midpoint of sleep) and next-day activity levels, accounting for the data's nested structure. Significant differences in activity levels were noted between workdays and nonworkdays, with WMA occurring approximately 1.08 hours earlier than PA during workdays (P<.001). Conversely, GMA was observed to commence about 1.22 hours later than PA (P<.001). Furthermore, a significant negative correlation was identified between the activity level of WMA and the previous night's midpoint of sleep (β=-0.263, P<.001), indicating that later bedtimes and wake times were linked to reduced activity levels in WMA the following day. However, there was no significant correlation between WMA's activity levels and total sleep time. Similarly, no significant correlations were found between the activity levels of PA and GMA and sleep indicators from the previous night. This study significantly advances the understanding of human biological rhythms by developing and highlighting GMA and WMA as key indicators, derived from human-smartphone interactions. These findings offer novel insights into how mental activities, alongside PA, are intricately linked to sleep patterns, emphasizing the potential of GMA and WMA in behavioral and health studies.

An updated model of shoot apical meristem regulation by ERECTA family and CLAVATA3 signaling pathways in Arabidopsis.

The shoot apical meristem (SAM) gives rise to the aboveground organs of plants. The size of the SAM is relatively constant due to the balance between stem cell replenishment and cell recruitment into new organs. In angiosperms, the transcription factor WUSCHEL (WUS) promotes stem cell proliferation in the central zone of the SAM. WUS forms a negative feedback loop with a signaling pathway activated by CLAVATA3 (CLV3). In the periphery of the SAM, the ERECTA family receptors (ERfs) constrain WUS and CLV3 expression. Here, we show that four ligands of ERfs redundantly inhibit the expression of these two genes. Transcriptome analysis confirmed that WUS and CLV3 are the main targets of ERf signaling and uncovered new ones. Analysis of promoter reporters indicated that the WUS expression domain mostly overlaps with the CLV3 domain and does not shift along the apical-basal axis in clv3 mutants. Our three-dimensional mathematical model captured gene expression distributions at the single-cell level under various perturbed conditions. Based on our findings, CLV3 regulates cellular levels of WUS mostly through autocrine signaling, and ERfs regulate the spatial expression of WUS, preventing its encroachment into the peripheral zone.

Effects of mesenchymal stem cells versus curcumin on sonic hedgehog signaling in experimental model of Hepatocellular Carcinoma.

Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC. The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology. In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.

Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching

Notch signaling guides vascular development and function by regulating diverse endothelial cell behaviors, including migration, proliferation, vascular density, endothelial junctions, and polarization in response to flow. Notch proteins form transcriptional activation complexes that regulate endothelial gene expression, but few of the downstream effectors that enable these phenotypic changes have been characterized in endothelial cells, limiting our understanding of vascular Notch activities. Using an unbiased screen of translated mRNA rapidly regulated by Notch signaling, we identified novel in vivo targets of Notch signaling in neonatal mouse brain endothelium, including UNC5B, a member of the netrin family of angiogenic-regulatory receptors. Endothelial Notch signaling rapidly upregulates UNC5B in multiple endothelial cell types. Loss or gain of UNC5B recapitulated specific Notch-regulated phenotypes. UNC5B expression inhibited endothelial migration and proliferation and was required for stabilization of endothelial junctions in response to shear stress. Loss of UNC5B partially or wholly blocked the ability of Notch activation to regulate these endothelial cell behaviors. In the developing mouse retina, endothelial-specific loss of UNC5B led to excessive vascularization, including increased vascular outgrowth, density, and branchpoint count. These data indicate that Notch signaling upregulates UNC5B as an effector protein to control specific endothelial cell behaviors and inhibit angiogenic growth.

Quantum double lock-in amplifier

Quantum lock-in amplifiers have been proposed to extract an alternating signal from a strong noise background. However, due to the typical target signal has unknown initial phase, it is challenging to extract complete information about the signal’s amplitude, frequency, and initial phase. Here, we present a general protocol for achieving a quantum double lock-in amplifier by employing two quantum mixers operating under orthogonal pulse sequences. To demonstrate the practical implementation, we discuss the experimental feasibility using a five-level double-Λ coherent population trapping system with Rb atoms. Here, each Λ structure acts as a quantum mixer, and two applied dynamical decoupling sequences serve as orthogonal reference signals. Notably, the system significantly reduces the total measurement time by nearly half and mitigates time-dependent systematic errors compared to conventional two-level systems. Furthermore, our quantum double lock-in amplifier is robust against experimental imperfections. This study establishes a pathway to alternating signal measurement, thereby facilitating the development of practical quantum sensing technologies.

Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia

This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, compares the entire expressed whole blood host transcriptome between Kenyan children (3-48 mos.) with non-SMA (Hb ≥ 6.0 g/dL, n = 39) and SMA (n = 18). Differential expression analyses reveal 1403 up-regulated and 279 down-regulated transcripts in SMA, signifying impairments in host inflammasome activation, cell death, and innate immune and cellular stress responses. Immune cell profiling shows decreased memory responses, antigen presentation, and immediate pathogen clearance, suggesting an immature/improperly regulated immune response in SMA. Module repertoire analysis of blood-specific gene signatures identifies up-regulation of erythroid genes, enhanced neutrophil activation, and impaired inflammatory responses in SMA. Enrichment analyses converge on disruptions in cellular homeostasis and regulatory pathways for the ubiquitin-proteasome system, autophagy, and heme metabolism. Pathway analyses highlight activation in response to hypoxic conditions [Hypoxia Inducible Factor (HIF)−1 target and Reactive Oxygen Species (ROS) signaling] as a central theme in SMA. These signaling pathways are also top-ranking in protein abundance measures and a Ugandan SMA cohort with available transcriptomic data. Targeted RNA-Seq validation shows strong concordance with our entire expressed transcriptome data. These findings identify key molecular themes in SMA pathogenesis, offering potential targets for new malaria therapies.

The total saponins from Chinese onion exert pronounced anti-hypercholesterolaemia activity in mice

AbstractChinese onion (Allium chinense G. Don) is an edible vegetable as well as a traditional Chinese medicine. It is rich in steroidal saponins and possesses broad health benefits. In this study, the optimal extraction protocol of the total saponins from Chinese onion (ACS) was explored, and the content of the total steroidal saponins in ACS reached 56.62%. Network pharmacology was applied to predict the related signalling pathways and targets between the main phytochemicals in ACS and hypercholesterolaemia. Enrichment analysis showed that ACS might intervene hypercholesterolaemia through the PI3K-Akt signalling pathway. Meanwhile, cholesterol-lowering effects were verified by ACS intervention in high-cholesterol diet-induced hypercholesterolaemia in Kunming mice. Compared with the model group, the TC and LDL-C levels of mice were decreased and the HDL-C level increased significantly after administration of ACS at a dose of 200 mg kg−1 day−1. The body weight gain, liver index, and atherosclerosis index all decreased dramatically. ACS could significantly reduce the fat content in the liver and reduce the number of fat droplets from the haematoxylin and eosin (H&amp;E) staining of mouse liver. The immunohistochemical staining indicated that ACS could up-regulate the expression of PI3K protein in the liver, thus playing an anti-hypercholesterolaemic role. This study indicated that ACS exhibited significant therapeutic and preventive effects on hypercholesterolaemia, and exerted anti-hypercholesterolaemia through the PI3K-Akt signalling pathway.

Image-driven evaluation metric for a space-based infrared diurnal detection analysis for flying aircrafts

The traditional evaluation calculation method fails to adequately consider the impact of image degradation and ignores the uncertainty caused by instrument noise on point target detectable status. This overestimates the detection capability of the system and cannot meet the needs of the point target detection evaluation under space-based observations. An image-driven evaluation metric (IDEM) is proposed in this paper, considering the effects of image degradation on the target, the background, and its clutter signals while providing coefficients of variation (CVs) for evaluation metrics. Image sequences of aircraft in different bands of the infrared imaging system were generated for cross validation. A comparative analysis against the traditional method shows that instrument noise significantly interferes with the point target signal in the image, and our method provides a more accurate and comprehensive evaluation of aircraft detectability under space-based infrared observations. Based on this, the IDEM maps under day and night in the mid- and long-infrared were computed and analyzed under space-based infrared observations of the flying aircraft. The results indicate that the mid-wave infrared (MWIR) is more sensitive to diurnal variation, whereas the long-wave infrared (LWIR) is more stable but has a lower daytime detectability compared to mid-infrared. Theoretically, both mid- and long-infrared enable night detection capabilities for point targets under the proper conditions, with mid-infrared offering higher detection potential. Our works provide new insight and approaches for the point target detection evaluation, system design, and on-orbit testing.

Dual-Regulation in Peroxisome and Cytoplasm toward Efficient Limonene Biosynthesis with Rhodotorula toruloides.

Rhodotorula toruloides is a potential workhorse for production of various value-added chemicals including terpenoids, oleo-chemicals, and enzymes from low-cost feedstocks. However, the limited genetic toolbox is hindering its metabolic engineering. In the present study, four type I and one novel type II peroxisomal targeting signal (PTS1/PTS2) were characterized and employed for limonene production for the first time in R. toruloides. The implant of the biosynthesis pathway into the peroxisome led to 111.5 mg/L limonene in a shake flask culture. The limonene titer was further boosted to 1.05 g/L upon dual-metabolic regulation in the cytoplasm and peroxisome, which included employing the acetoacetyl-CoA synthase NphT7, adding an additional copy of native ATP-dependent citrate lyase, etc. The final yield was 0.053 g/g glucose, which was the highest ever reported. The newly characterized PTSs should contribute to the expansion of genetic toolboxes forR. toruloides. The results demonstrated that R. toruloides could be explored for efficient production of terpenoids.

Lycopene alleviates Bisphenol a-induced lipid accumulation via activating the SIRT1/PGC-1α signaling in PK15 cells

The present study sought to investigate the protective effect of Lycopene (LYC) on Bisphenol A (BPA)-induced lipid accumulation and elucidate the potential molecular mechanism. In vitro, the PK15 cells with or without LYC were exposed to BPA for 6 h to detect the lipid accumulation using Nile red’s and Oil Red O’ staining. Meanwhile, redox status, mitochondrial function, gene expression and protein levels relating to lipid accumulation were evaluated by cellular biochemical assays, immunofluorescence staining, quantitative real-time PCR (qRT-PCR) and Western blot, respectively. In addition, ROS scavenger N-acetylcysteine (NAC), SIRT1 inhibitor EX527, SIRT1 siRNA and PGC-1α siRNA were used to verify the target signaling pathways responsible for the protective effect of LYC against BPA-indcued lipid accumulation. In vivo, the twenty four male Wistar rats were randomly divided into three groups, received either BPA (50 mg/kg/day BW) or LYC (10 mg/kg/day BW) orally for 60 days. The kidney tissues were evaluated by HE’s and Oil Red O’s staining, lipid-associated genes and proteins expression were detected through qRT-PCR and Western blot. The results showed that BPA-exposed PK15 cells and rats had increased lipid droplets with elevated transcription of lipogenic factors SREBP1 and PPARγ, and down-regulated PPARα expression, and which is accompanied by redox imbalance and abnormal mitochondrial function. Conversely, LYC prevented BPA-induced lipid metabolism disorder and lipid accumulation through impeding ROS overproduction. Moreover, PK15 cells and rats exposed to BPA showed decrease in SIRT1 and PGC-1α levels, whereas LYC blocked the decrease of SIRT1 and PGC-1α protein levels. Furthermore, inhibition or silence of SIRT1 and PGC-1α abrogated the improvements of LYC on ROS generation, mitochondrial mass impairement and lipid accumulation in BPA-treated PK15 cells. Collectively, these findings indicate that SIRT1/PGC-1α signaling pathway is involved in the protective effect of LYC on BPA-induced lipid accumulation. These results also provide a potential promising therapeutic of LYC against BPA-induced lipid accumulation in kidney cells and organs.

Pathway analysis of peripheral blood CD8+ T cell transcriptome shows differential regulation of sphingolipid signaling in multiple sclerosis and glioblastoma.

Multiple sclerosis (MS) and glioblastoma (GBM) are CNS diseases in whose development and progression immune privilege is intimately important, but in a relatively opposite manner. Maintenance and strengthening of immune privilege have been shown to be an important mechanism in glioblastoma immune evasion, while the breakdown of immune privilege leads to MS initiation and exacerbation. We hypothesize that molecular signaling pathways can be oppositely regulated in peripheral blood CD8+ T cells of MS and glioblastoma patients at a transcriptional level. We analyzed publicly available data of the peripheral blood CD8+ T cell MS vs. control (MSvsCTRL) and GBM vs. control (GBMvsCTRL) differentially expressed gene (DEG) contrasts with Qiagen's Ingenuity pathway analysis software (IPA). We have identified sphingolipid signaling pathway which was significantly downregulated in the GBMvsCTRL and upregulated in the MSvsCTRL. As the pathway is important for the CD8+ T lymphocytes CNS infiltration, this result is in line with our previously stated hypothesis. Comparing publicly available lists of differentially expressed serum exosomal miRNAs from MSvsCTRL and GBMvsCTRL contrasts, we have identified that hsa-miR-182-5p has the greatest potential effect on sphingolipid signaling regarding the number of regulated DEGs in the GBMvsCTRL contrast, while not being able to find any relevant potential sphingolipid signaling target transcripts in the MSvsCTRL contrast. We conclude that the sphingolipid signaling pathway is a top oppositely regulated pathway in peripheral blood CD8+ T cells from GBM and MS, and might be crucial for the differences in CNS immune privilege maintenance of investigated diseases, but further experimental research is necessary.

Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity

ObjectivesCo-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. MethodsMice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. ResultsDicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. ConclusionsOur study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.