miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Arg177 and Asp159 from dog prion protein slow liquid-liquid phase separation and inhibit amyloid formation of human prion protein.

Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrPC) to ß-sheet-rich pathological aggregated form of PrPSc in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrPC contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrPC condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrPC, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrPC, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrPC liquid-phase condensation.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer.

After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.

Small-Intensity Rainfall Triggers Greater Contamination of Rubber-Derived Chemicals in Road Stormwater Runoff from Various Functional Areas in Megalopolis Cities.

Rubber-derived chemicals (RDCs) originating from tire and road wear particles are transported into road stormwater runoff, potentially threatening organisms in receiving watersheds. However, there is a lack of knowledge on time variation of novel RDCs in runoff, limiting initial rainwater treatment and subsequent rainwater resource utilization. In this study, we investigated the levels and time-concentration profiles of 35 target RDCs in road stormwater runoff from eight functional areas in the Greater Bay Area, South China. The results showed that the total concentrations of RDCs were the highest on the expressway compared with other seven functional areas. N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), 6PPD-quinone, benzothiazole, and 1,3-diphenylguanidine were the top four highlighted RDCs (ND-228840 ng/L). Seasonal and spatial differences revealed higher RDC concentrations in the dry season as well as in less-developed regions. A lag effect of reaching RDC peak concentrations in road stormwater runoff was revealed, with a lag time of 10-90 min on expressways. Small-intensity rainfall triggers greater contamination of rubber-derived chemicals in road stormwater runoff. Environmental risk assessment indicated that 35% of the RDCs posed a high risk, especially PPD-quinones (risk quotient up to 2663). Our findings contribute to a better understanding of managing road stormwater runoff for RDC pollution.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Aflatoxin B1 inhibited the development of primary myoblasts of grass carp (Ctenopharyngodon idella) by degrading extracellular matrix.

According to the International Agency for Research on Cancer (IARC), aflatoxin B1 (AFB1) has been recognized as a major contaminant in food and animal feed and which is a common mycotoxin with high toxicity. Previous research has found that AFB1 inhibited zebrafish muscle development. However, the potential mechanism of AFB1 on fish muscle development is unknown, so it is necessary to conduct further investigation. In the present research, the primary myoblast of grass carp was used as a model, we treated myoblasts with AFB1 for 24 h. Our results found that 5 µM AFB1 significantly inhibited cell proliferation and migration (P < 0.05), and 10 µM AFB1 promoted lactate dehydrogenase (LDH) release (P < 0.05). Reactive oxygen species (ROS), protein carbonyl (PC) and malondialdehyde (MDA) levels were increased in 15, 5 and 10 µM AFB1 (P < 0.05), respectively. Catalase (CAT), glutathione peroxidase (GPx) and total superoxide dismutase (T-SOD) activities were decreased in 10, 10 and 15 µM AFB1 (P < 0.05), respectively. Furthermore, 15 µM AFB1 induced oxidative damage by Nrf2 pathway, also induced apoptosis in primary myoblast of grass carp. Meanwhile, 15 µM AFB1 decreased MyoD gene and protein expression (P < 0.05). Importantly, 15 µM AFB1 decreased the protein expression of collagen Ⅰ and fibronectin (P < 0.05), and increased the protein levels of urokinase plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), and p38 mitogen-activated protein kinase (p38MAPK) (P < 0.05). As a result, our findings suggested that AFB1 damaged the cell morphology, induced oxidative damage and apoptosis, degraded ECM components, in turn inhibiting myoblast development by activating the p38MAPK/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase (MMPs)/extracellular matrix (ECM) signaling pathway.

Bayesian estimation of dissipation and sound speed in tube measurements using a transfer-function model.

This study discusses acoustic dissipation, which contributes to inaccuracies in impedance tube measurements. To improve the accuracy of these measurements, this paper introduces a transfer function model that integrates diverse dissipation prediction models. Bayesian inference is used to estimate the important parameters included in these models, describing dissipation originating from various mechanisms, sound speed, and microphone positions. By using experimental measurements and considering a hypothetical air layer in front of a rigid termination as the material under test, Bayesian parameter estimation allows a substantial enhancement in characterization accuracy by incorporating the dissipation and sound speed estimates. This approach effectively minimizes residual absorption coefficients attributed to both boundary-layer effects and air medium relaxation. The incorporation of dissipation models leads to a substantial reduction (to 1%) in residual absorption coefficients. Moreover, the use of accurately estimated parameters further enhances the accuracy of actual tube measurements of materials using the two-microphone transfer function method.

Promoter of Cassava MeAHL31 Responds to Diverse Abiotic Stresses and Hormone Signals in Transgenic Arabidopsis.

The AT-hook motif nuclear-localized (AHL) family is pivotal for the abiotic stress response in plants. However, the function of the cassava AHL genes has not been elucidated. Promoters, as important regulatory elements of gene expression, play a crucial role in stress resistance. In this study, the promoter of the cassava MeAHL31 gene was cloned. The MeAHL31 protein was localized to the cytoplasm and the nucleus. qRT-PCR analysis revealed that the MeAHL31 gene was expressed in almost all tissues tested, and the expression in tuber roots was 321.3 times higher than that in petioles. Promoter analysis showed that the MeAHL31 promoter contains drought, methyl jasmonate (MeJA), abscisic acid (ABA), and gibberellin (GA) cis-acting elements. Expression analysis indicated that the MeAHL31 gene is dramatically affected by treatments with salt, drought, MeJA, ABA, and GA3. Histochemical staining in the proMeAHL31-GUS transgenic Arabidopsis corroborated that the GUS staining was found in most tissues and organs, excluding seeds. Beta-glucuronidase (GUS) activity assays showed that the activities in the proMeAHL31-GUS transgenic Arabidopsis were enhanced by different concentrations of NaCl, mannitol (for simulating drought), and MeJA treatments. The integrated findings suggest that the MeAHL31 promoter responds to the abiotic stresses of salt and drought, and its activity is regulated by the MeJA hormone signal.

Soy protein nanoparticles prepared by enzymatic cross-linking with enhanced emulsion stability.

Particle-stabilized emulsions have shown increasing potential application in food emulsion systems. Here, soy protein, an abundant and inexpensive plant-based protein, was used to develop nanoparticles for emulsion stabilizer applications. An enzymatic cross-linking method based on microbial transglutaminase (mTG) was developed for the fabrication of soy protein nanoparticles (SPNPs). The emulsion stability was compared between soy protein isolate (SPI) and three different nanoparticles. The size of SPNPs ranged from 10 nm to 40 nm, depending on the production conditions. The emulsions stabilized by SPNPs were stable for at least 20 days at room temperature, whereas the emulsion that was stabilized by SPI showed a significant creaming and phase separation phenomenon. The SPNPs also showed a higher antioxidant and reducing effect compared to SPI. The use of mTG induced cross-linking resulted in the formation of covalent bonding between protein molecules, and led to the formation of nanoparticles with higher stability. The approaches support the utilization of inexpensive and abundant plant-based resources as emulsion stabilizers in food applications.

Description of Flavimaribacter sediminis gen. nov., sp. nov., a New Member of the Family Rhizobiaceae Isolated from Marine Sediment.

A novel Gram-staining-negative, aerobic and rod-shaped bacterium, designated WL0058T, was isolated from coastal sediment sample collected in Nantong city, Jiangsu province of China (120° 51' 13″ E, 32° 6' 26″ N) in October 2020. Strain WL0058T was found to grow at 4-37 °C (optimum, 28 °C) with 1.5-4.0% NaCl (optimum, 4.0%) and displayed alkaliphilic growth with the pH range of pH 6.0-10.0 (optimum, pH 6.0). Phylogenetic trees constructed based on 16S rRNA gene sequence indicated that strain WL0058T is a member of the family Rhizobiaceae, shared the highest similarity with "Hoeflea prorocentri" CCTCC AB 2016294T (97.7%) and constituted a sub-cluster within the family with it, while the similarity with others in the family Rhizobiaceae was lower than 97.0%. The G + C content of genomic DNA was 59.5 mol%. Polar lipids profile of strain WL0058T included phosphatidylcholine (PC), phosphatidylethanolamine (PE), and glycolipid (GL), phosphatidylmonomethylethanolamine (PME) and two unidentified polar lipids (L). The major isoprenoid quinone was determined to be Q-10 and the major fatty acids were C16:0, C18:0, summed features 4 (iso-C17:1 and/or anteiso-C17:1), and summed features 8 (C18:1ω6c and/or C18:1ω7c). As inferred from the morphology, physiology, and biochemical analysis, genotypic characteristics, and the phylogenetic trees, strain WL0058T ought to be recognized as a novel genus in the family Rhizobiaceae, for which the name Flavimaribacter sediminis gen. nov., sp. nov. The type strain of Flavimaribacter sediminis gen. nov., sp. nov. is WL0058T (= MCCC 1K06063T = JCM 34659T = GDMCC 1.2448T).

Introduction to the special issue on 3D sound reconstruction for virtual auditory displays: Applications in buildingsa).

This special issue on three-dimensional (3D) sound reconstruction for virtual auditory displays: applications in buildings contains six research papers. Among them, three articles describe virtual reconstruction of important theatres and opera houses. The remaining articles focus on theoretical approaches of virtual sound localization or auralization.

Validation of Bayesian design for broadband microslit panel absorbers using causal inference.

This paper discusses experimental validations of multilayer microslit panels (MSPs) designed via Bayesian inference to obtain both high sound absorption and wide bandwidth simultaneously. Microslit perforation in thin panels is similar to microperforated panels [Xiang, Fackler, Hou, and Schmitt (2022). J. Acoust. Soc. Am. 151(5), 3094-3103]. MSP absorbers in single-layer configurations are functioning in a limited frequency range. By stacking the MSPs in multiple layered structures, absorbing performance may be widened in frequency ranges while retaining high absorption coefficients. Besides design challenges of multiple MSPs in layered structures to fulfill a practical requirement and minimize fabrication complexity, this paper further discusses challenges in experimental validations when experimental results undesirably deviate from the initial Bayesian design. Causation analysis is applied to the validation efforts where a causal model-based inference effectively provides causal reasoning of fabrication inaccuracies. Along with the causal inference, a causal reasoning conducted in this work can guide corrections due to fabrication inaccuracies during the iterative validation process.

The In Situ Preparation of Ni-Zn Ferrite Intercalated Expanded Graphite via Thermal Treatment for Improved Radar Attenuation Property.

The composites of expanded graphite (EG) and magnetic particles have good electromagnetic wave attenuation properties in the centimeter band, which is valuable in the field of radar wave interference. In this paper, a novel preparation method of Ni-Zn ferrite intercalated EG (NZF/EG) is provided in order to promote the insertion of Ni-Zn ferrite particles (NZF) into the interlayers of EG. The NZF/EG composite is in situ prepared via thermal treatment of Ni-Zn ferrite precursor intercalated graphite (NZFP/GICs) at 900 °C, where NZFP/GICs is obtained through chemical coprecipitation. The morphology and phase characterization demonstrate the successful cation intercalation and NZF generation in the interlayers of EG. Furthermore, the molecular dynamics simulation shows that the magnetic particles in the EG layers tend to disperse on the EG layers rather than aggregate into larger clusters under the synergy of van der Waals forces, repulsive force, and dragging force. The radar wave attenuation mechanism and performance of NZF/EG with different NZF ratios are analyzed and discussed in the range of 2-18 GHz. The NZF/EG with the NZF ratio at 0.5 shows the best radar wave attenuation ability due to the fact that the dielectric property of the graphite layers is well retained while the area of the heterogeneous interface is increased. Therefore, the as-prepared NZF/EG composites have potential application value in attenuating radar centimeter waves.

Organizing Pneumonia in A Patient Double-Positive for ANCA and Anti-GBM Antibodies: A Case Report.

Both anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are common causes of pulmonary-renal syndrome. Organizing pneumonia (OP), a special pattern of interstitial lung disease, is extremely rare either in AAV or anti-GBM disease. We report an old woman presented with OP on a background of co-presentation with both ANCA and anti-GBM antibodies.

Optical coherence tomography angiography for the detection and evaluation of ptic disc neovascularization: a retrospective, observational study.

BACKGROUND: To assess and characterize neovascularization of the optic disc (NVD) using optical coherence tomography angiography (OCTA) and different OCTA-based methods. METHODS: This retrospective, observational study included patients who were suspected of having early PDR with no presence of clinically apparent neovascularization (NV) bur were clinically diagnosed with proliferative diabetic retinopathy (PDR), or severe NPDR. Patients underwent standard clinical examinations and OCTA imaging using a 6 × 6 montage scan. Two trained graders identified NVD using different imaging systems (ultra-widefield-colour fundus photography (UWF-CFP), OCT, OCTA and fluorescein angiography (FA)). Moreover, morphological classification of NVD was performed. The detection and morphological classification of NVD by different OCTA-based methods (B-scan OCTA, En-face OCTA, VRI Angio and VRI Structure) were compared. RESULTS: A total of 169 eyes (126 eyes with PDR and 43 eyes with severe NPDR) of 123 participants were included in this study. The detection rate of NVD was 34.91% by UWF-CFP compared with 59.76% by OCT, 59.76% by OCTA, and 62.72% by FA. After excluding 2 cases with epiretinal membranes, the NVD diagnosis detected by OCT was used as the standard. Among 99 eyes diagnosed with NVD by OCT, B-scan OCTA detected NVD with a sensitivity of 97.98%, which was higher than that by en face OCTA (80.81%), VRI Angio (65.66%), and VRI Structure (61.62%) (all P < 0.05). According to its characteristics on OCTA, NVD was divided into four types (12 cases of type I, 6 cases of type II, 39 cases of type III, and 42 cases of type IV). For type I, B-scan OCTA exhibited a higher diagnostic sensitivity than other methods (P < 0.05). For types II and IV, there were no statistically significant differences in the sensitivity of various methods between the two groups (P > 0.05). CONCLUSION: OCTA and different OCTA-based methods are significant to the diagnosis of NVD, and the diagnostic accuracy of different detection methods may be related to different types of NVD.

Wide-field swept-source OCTA in the assessment of retinal microvasculature in early-stage diabetic retinopathy.

BACKGROUND: To perform a quantitative analysis of retinal microvasculature in patients with early-stage diabetic retinopathy (DR) using wide-field swept-source optical coherence tomography angiography (SS-OCTA).  METHODS: One hundred nineteen eyes of 119 patents (67 eyes with no DR and 52 eyes with mild-moderate nonproliferative diabetic retinopathy (NPDR)) were enrolled in this observational and cross-sectional cohort study, and an age-matched group consisting of 39 eyes of 39 non-diabetic subjects were set as the control. Each participant underwent a full ophthalmic examination, including wide-field SS-OCTA imaging. On OCTA scans (12 mm * 12 mm), the mean perfusion area (PA) and vessel density (VD) were independently measured in all 16 Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. Linear regression analyses were conducted to evaluate the influences of PA. RESULTS: In the central ring, there were no significant differences in the average PA and VD among the groups. In the 3 mm radius, the PA and VD of the no DR and mild-moderate NPDR were significantly decreased compared with the control group in superior and inferior quadrants. In the wide-field scans (9 and 12 mm radius), there was no significant difference in average PA and VD between the groups in each sectors (p > 0.05). Regression analysis found that the effect of VD on PA was statistically different (b = 1.311, p < 0.001). CONCLUSION: Wide-field OCTA imaging is useful for evaluating peripheral capillary perfusion in eyes with early-stage DR. Decrease in PA and VD was greater in the S3 and I3 sectors, and reductions in PA and VD were uneven in wide-filed sectors (9 and 12 mm radius).

Bayesian design of broadband multilayered microperforated panel absorbers.

In some noise control and architectural acoustics applications, nonfibrous, hygienic materials are desirable or even strictly required. In meeting such restrictive requirements, microperforated panel (MPP) sound absorbers represent a potential solution. Yet, they typically possess limited absorption bandwidth. Combining multiple MPPs into a multilayer system may broaden the absorption frequency ranges while maintaining high absorption. When increasing the overall absorption bandwidth, each additional MPP layer also increases the complexity of the design process because the design parameters are correspondingly increased by four per each additional layer. This paper applies a Bayesian inferential framework to the design of multilayer MPP absorbers with a parsimonious structural configuration, which penalizes the overlayered configurations. This Bayesian framework demonstrates that the practical design of multilayer MPP absorbers may be accomplished with two levels of model-based inference: model selection and parameter estimation. The design process proceeds inversely from a design target to design parameters, including the required number of MPP layers and their corresponding MPP parameters. This paper discusses the Bayesian design formulation, unified implementation of two levels of Bayesian inference, and experimental validation of a Bayesian design for a multilayered MPP absorber, which is able to meet the design target arising from practice.

Plant-Derived Molecule 4-Methylumbelliferone Suppresses FcεRI-Mediated Mast Cell Activation and Allergic Inflammation.

Mast cells (MCs) are an important treatment target for high-affinity IgE Fc receptor (FcεRI)-mediated allergic diseases. The plant-derived molecule 4-methylumbelliferone (4-MU) has beneficial effects in animal models of inflammation and autoimmunity diseases. The aim of this study was to examine 4-MU effects on MC activation and probe the underlying molecular mechanism(s). We sensitized rat basophilic leukemia cells (RBLs) and mouse bone marrow-derived mast cells (BMMCs) with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated them with exposure to DNP-human serum albumin (HSA), and then treated stimulated cells with 4-MU. Signaling-protein expression was determined by immunoblotting. In vivo allergic responses were examined in IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) mouse models. 4-MU inhibited ß-hexosaminidase activity and histamine release dose-dependently in FcεRI-activated RBLs and BMMCs. Additionally, 4-MU reduced cytomorphological elongation and F-actin reorganization while down-regulating IgE/Ag-induced phosphorylation of SYK, NF-κB p65, ERK1/2, p38, and JNK. Moreover, 4-MU attenuated the PCA allergic reaction (i.e., less ear thickening and dye extravasation). Similarly, we found that 4-MU decreased body temperature, serum histamine, and IL4 secretion in OVA-challenged ASA model mice. In conclusion, 4-MU had a suppressing effect on MC activation both in vitro and in vivo and thus may represent a new strategy for treating IgE-mediated allergic conditions.