Mechanism Of Modulation Research Articles

Mechanism of acid-sensing ion channel modulation by Hi1a.

Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by extracellular acidification. Amongst many pathological roles, ASICs are an important mediator of ischemic cell death and hence an attractive drug target for stroke treatment as well as other conditions. A peptide called Hi1a, isolated from Australian funnel web spider venom, inhibits ASIC1a and attenuates cell death in a stroke model up to 8 h after stroke induction. Here, we set out to understand the molecular basis for Hi1a's action. Hi1a is a bivalent toxin with two inhibitory cystine knot domains joined by a short linker. We found that both Hi1a domains modulate human ASIC1a gating with the N-terminal domain impairing channel activation while the C-terminal domain produces a "pro-open" phenotype even at submicromolar concentrations. Interestingly, both domains bind at the same site since a single point mutation, F352A, abolishes functional effects and reduces toxin affinity in surface plasmon resonance measurements. Therefore, the action of Hi1a at ASIC1a appears to arise through a mutually exclusive binding model where either the N or C domain of a single Hi1a binds one ASIC1a subunit. An ASIC1a trimer may bind several inhibitory N domains and one or more pro-open C domains at any one time, accounting for the incomplete inhibition of wild type Hi1a. We also found that the functional differences between these two domains are partially transferred by mutagenesis, affording new insight into the channel function and possible novel avenues of drug design.

Exploring the Crystal Structure and Electronic Properties of γ-Al2O3: Machine Learning Drives Future Material Innovations.

For decades, researchers have struggled to determine the precise crystal structure of γ-Al2O3 due to its atomic-level disorder and the challenges associated with obtaining high-purity, high-crystallinity γ-Al2O3 in laboratory settings. This study investigates the crystal structure and electronic properties of γ-Al2O3 coatings under the influence of an external electric field, integrating machine learning with density functional theory (DFT). A potential 160-atom supercell structure was identified from over 600,000 γ-Al2O3 configurations and confirmed through high-resolution transmission electron microscopy and selected area electron diffraction. The findings indicate that γ-Al2O3 deviates from the conventional spinel structure, suggesting that octahedral vacancies can reduce the system's energy. Under an external electric field, the material's band structure and density of states (DOS) undergo significant changes: the bandgap narrows from 3.996 to 0 eV, resulting in metallic behavior, while the projected density of states (PDOS) exhibits peak broadening and splitting of oxygen atom PDOS below the Fermi level. These alterations elucidate the variations in the electrical conductivity of alumina coatings under an electric field. These findings clarify the mechanisms of γ-Al2O3's electronic property modulation and offer insights into its covalent and ionic mixed bonding as a wide-bandgap semiconductor. This discovery is essential for understanding dielectric breakdown in insulating materials.

Immediate modulatory effects of transcutaneous vagus nerve stimulation on patients with Parkinson’s disease: a crossover self-controlled fMRI study

BackgroundPrevious studies have evaluated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of Parkinson’s disease (PD). However, the mechanism underlying the effect of taVNS on PD remains to be elucidated. This study aimed to investigate the immediate effects of taVNS in PD patients.MethodsThis crossover self-controlled study included 50 PD patients. Each patient underwent three sessions of resting-state functional magnetic resonance imaging (rs-fMRI) under three conditions: real taVNS, sham taVNS, and no taVNS intervention. We analyzed whole-brain amplitude of low-frequency fluctuations (ALFF) from preprocessed fMRI data across different intervention conditions. ALFF values in altered brain regions were correlated with clinical symptoms in PD patients.ResultsForty-seven participants completed the study and were included in the final analysis. Real taVNS was associated with a widespread decrease in ALFF in the right hemisphere, including the superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus (voxel p < 0.001, GRF corrected). The ALFF value in the right superior parietal lobule during real taVNS was negatively correlated with the Unified Parkinson’s Disease Rating Scale Part III (r = −0.417, p = 0.004, Bonferroni corrected).ConclusionTaVNS could immediately modulate the functional activity of brain regions involved in superior parietal lobule, precentral gyrus, postcentral gyrus, middle occipital gyrus, and cuneus. These findings offer preliminary insights into the mechanism of taVNS in treating PD and bolster confidence in its long-term therapeutic potential. TaVNS appears to reduce ALFF values in specific brain regions, suggesting a potential modulation mechanism for treating PD.

Light-modulated van der Waals force microscopy

Atomic force microscope generally works by manipulating the absolute magnitude of the van der Waals force between tip and specimen. This force is, however, less sensitive to atom species than to tip-sample separations, making compositional identification difficult, even under multi-modal strategies or other atomic force microscopy variations. Here, we report the phenomenon of a light-modulated tip-sample van der Waals force whose magnitude is found to be material specific, which can be employed to discriminate heterogeneous compositions of materials. We thus establish a near-field microscopic method, named light-modulated van der Waals force microscopy. Experiments discriminating heterogeneous crystalline phases or compositions in typical materials demonstrate a high compositional resolving capability, represented by a 20 dB signal-to-noise ratio on a MoTe2 film under the excitation of a 633 nm laser of 1.2 mW, alongside a sub-10 nm lateral spatial resolution, smaller than the tip size of 20 nm. The simplicity of the light modulation mechanism, minute excitation light power, broadband excitation wavelength, and diversity of the applicable materials imply broad applications of this method on material characterization, particularly on two-dimensional materials that are promising candidates for next-generation chips.

Denervation‑induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway.

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro‑computed tomography, histochemical staining, RNA‑sequencing, reverse transcription‑quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve‑injured muscle tissue‑derived fibro‑adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis‑associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury‑induced muscle HO.

Origami multifunctional metagrating for a mechanically controlled electromagnetic wavefront

Metasurface or artificial electromagnetic (EM) structures offer viable options for manipulating EM waves with compact periodic structures. Tunable metasurfaces are ideal for many engineering and scientific applications because they can manipulate EM wavefronts. However, it is challenging to implement tunable metasurfaces that can achieve multiple functions for integration. In addition, integrated multifunctional metasurfaces are often structurally complicated and bulky. This paper proposes a simple spatial modulation mechanism that uses Miura origami reconfigurable one-dimensional metagrating to achieve multiple control of EM wavefront. Theoretical predictions, numerical simulations, and experiments confirm and validate the basic concepts. In particular, the continuous geometric deformation of the Miura-ori lattice is a promising method for compensating the dispersion of characters in gradient metasurfaces. Considering origami structures’ outstanding mechanical properties and strong deformation abilities, this discovery opens up another avenue for lightweight and deployable meta-devices.

Mutant amplitude modulation behavior of MIS-like structure of few-layer graphene/SiO2/p-Si in 500–750 GHz band

Graphene has great application potential in the field of electromagnetic modulation field because of its excellent physical and electronic properties. Studies have demonstrated that the properties of graphene films with different layers are also different due to the difference in energy band structure. Nowadays, the modulation mechanism of monolayer graphene (MLG) and bilayer graphene (BLG) has been gradually discovered, but for graphene with more than three layers, the mechanism of whether it is tunable remains to be explored, especially on the proving from an experimental perspective. In this study, the CVD-prepared highly homogeneous few-layer graphene (FLG) film was combined with SiO2 nanolayers and P-doped Si substrate to form an MIS-like capacitor structure, a unique electromagnetic behavior of mutant amplitude modulation exhibited by FLG film was found, which was different from that of mono- and bi-layers of graphene. The results show that the structure exhibits obvious modulation behavior in the ultra-wideband frequency of 500–750 GHz and the bias of 0.9 V, up to 3.1 dB. This study makes a new supplement to a gap in the EM modulation system of graphene series material.

Pixel-wise matching cost function for robust light field depth estimation

Depth estimation has significant potential in industrial applications, such as robot navigation. Light Field (LF) technology captures both spatial and angular information of a scene, enabling precise depth acquisition. Stereo matching technology has been commonly used for this task in LF imaging. However, previous methods typically compute the matching cost by simply shifting images with predefined offsets, causing poor performance in regions with sudden depth distribution changes (e.g., edges). To address this issue, we propose a Pixel-wise Matching Cost Function (PMCF) to estimate depth in units of pixel, then design a pixel-based network, termed PixelNet, for depth prediction, which achieves top rankings on the HCI 4D light field benchmark. Specifically, our cost function consists of two modules: the range search strategy and the modulation mechanism. The range search strategy enables the network to iteratively optimize depth on a per-pixel basis, while the modulation mechanism effectively handles scene noise and occlusions. By integrating these two modules, our function enables the generation of depth maps with sharper edges and smoother surfaces, compared with previous methods. Finally, we design a pixel-based network and apply it to both synthetic and real-world scenes, demonstrating that our method outperforms state-of-the-art methods in both scenes. Furthermore, PixelNet can also function as a post-processing network that can be seamlessly integrated with existing methods for depth refinement.

Point cloud upsampling network based on pyramid pooling and self-attention mechanism

For the problems of irregular point cloud data and non-unique input size, a point-cloud upsampling network (PPSA-PU) based on Pyramid Pooling and Self-Attention mechanism is proposed. Multi-scale features are first extracted from the input point cloud using dense map convolution with different expansion rates, and the pyramid pooling module and self-attention mechanism are added. By applying the same pooling operation to regions of different sizes and numbers, the network is made to accept inputs of arbitrary size. Self-attention is used to weight the features to establish global correlation and improve the feature extraction capability. The features are then extended by the Self-Attention NodeShuffle (SA-NS) module, which uses a graph convolution layer to fuse neighbour information and learn new point features from the latent space. Finally, the coordinate reconstruction module is used to generate a dense up-sampled point cloud. Using the existing dataset to train and test the network and compare it with the existing up-sampling network, the experimental results show that PPSA-PU is better in terms of evaluation metrics and performance, and has better generalisation and robustness.

Research on Efficient Electromagnetic Shielding Performance and Modulation Mechanism of Aero/Organo/Hydrogels with Gravity-Induced Asymmetric Gradient Structure.

To eliminate electromagnetic pollution, it is a challenging task to develop highly efficient electromagnetic shielding materials that integrate microwave absorption (MA) performance with high shielding capability and achieve tunability in shielding performance. Asymmetrically structured aero/organo/hydrogels with a progressively changing concentration gradient of liquid metal nanoparticles (LMNPs), induced by gravity, are prepared by integrating the conductive fillers Ti3C2Tx MXene and LMNPs into a dual-network structure composed of polyvinyl alcohol and cellulose nanofibers. Benefiting from the unique structure, which facilitates the absorption-reflection-reabsorption process of electromagnetic waves along with conductive fillers and the porous structure, three types of gels demonstrate efficient shielding performance. HPCML achieves a total shielding effectiveness (SET) of up to 86.9dB and a reflection shielding effectiveness (SER) of as low as 2.85dB. Especially, APCML, with an ultra-low reflection coefficient (R) of 6.4%, achieves compatibility between shielding performance and MA properties. The relationship between dispersing media (air, water, and glycerol/water) and the shielding performance of aero/organo/hydrogels is explored, thereby achieving modulation of the shielding performance of the gel system. The work has paved a clear path for integrating absorption and shielding capabilities into a composite material, thereby providing a prototype of a highly efficient shielding material with MA performance.

Chaotic band-gap modulation mechanism for nonlinear vibration isolation systems based on time-delay feedback control

Abstract Systems designed for nonlinear vibration isolation that incorporate chaotic states demonstrate superior capabilities in vibration attenuation, adeptly modulating the spectral constituents of vibrational noise. Yet, the challenge of eliciting low-amplitude chaotic dynamics and perpetuating these states across a diverse array of parameters remains formidable. This study proposes a pioneering strategy and technique for modulating the chaos band by incorporating a time-delayed feedback control mechanism within the framework of nonlinear vibration isolation systems.The investigation commences with an exhaustive analysis of the nonlinear dynamics, shedding light on the principles dictating the evolution of chaos. The study then advances to scrutinize the dynamics of systems with delays to elucidate the chaos-inducing processes engendered by feedback with temporal lags. Building upon the system’s responses, the chaotic performance and the effectiveness of the vibration isolation are crafted. Consequently, the time-delayed feedback control parameters are identified as pivotal design variables, which are then employed to dissect the control mechanisms influenced by the time-delayed feedback on the chaos band. Utilizing the delineated control mechanism, the nonlinear vibration isolation system is precipitously transitioned from a state of stable periodicity to one of chaos, fostering low-amplitude chaotic dynamics across an expansive parameter space, and in turn, resolving the previously stated challenge. Perhaps most significantly, the mechanism for attaining low-amplitude chaos introduced here paves the way for innovative methodologies in the active vibration isolation design of similar systems. Furthermore, it is anticipated to yield theoretical guidance for the manipulation of chaos bands and the formulation of active vibration isolation strategies within the domain of nonlinear vibration isolation systems.

All-optical broadband terahertz modulator based on CdS NWs/Si heterojunction and interface photoconductivity analysis

A high-performance, low-cost terahertz modulator is fabricated by spin-coating CdS nanowires onto silicon. This all-optical modulator achieves broadband modulation (0.4–1.6 THz) with a significant depth of 85% at a low power density (2 W cm−2), exceeding bare silicon by fourfold. THz-TDS confirms its terahertz amplitude modulation capability. Tests of the simple photonic switch further illustrate the modulator’s potential for carrying information on a terahertz transmission wave. The modulation mechanism is explained through energy band theory and photoconductivity data. This work also presents a novel method for probing heterostructure formation using THz-TDS with laser irradiation.

Immune Implications of Cholesterol-Containing Lipid Nanoparticles.

The majority of clinically approved nanoparticle-mediated therapeutics are lipid nanoparticles (LNPs), and most of these LNPs are liposomes containing cholesterol. LNP formulations significantly alter the drug pharmacokinetics (PK) due to the propensity of nanoparticles for uptake by macrophages. In addition to readily engulfing LNPs, the high expression of cholesterol hydroxylases and reactive oxygen species (ROS) in macrophages suggests that they will readily produce oxysterols from LNP-associated cholesterol. Oxysterols are a heterogeneous group of cholesterol oxidation products that have potent immune modulatory effects. Oxysterols are implicated in the pathogenesis of atherosclerosis and certain malignancies; they have also been found in commercial liposome preparations. Yet, the in vivo metabolic fate of LNP-associated cholesterol remains unclear. We review herein the mechanisms of cellular uptake, trafficking, metabolism, and immune modulation of endogenous nanometer-sized cholesterol particles (i.e., lipoproteins) that are also relevant for cholesterol-containing nanoparticles. We believe that it would be imperative to better understand the in vivo metabolic fate of LNP-associated cholesterol and the immune implications for LNP-therapeutics. We highlight critical knowledge gaps that we believe need to be addressed in order to develop safer and more efficacious lipid nanoparticle delivery systems.

A sequential binding mechanism for 5′ splice site recognition and modulation for the human U1 snRNP

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how human U1 snRNP recognizes particular 5′ splice sites (5′SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5′SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5′SS modulation. We have determined a sequential binding mechanism for modulation of −1A bulged 5′SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged with a −1A bulged 5′SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5′SS complexes. Branaplam targets a ribonucleoprotein, not only an RNA duplex, and its action depends on fundamental properties of 5′SS recognition.

Qingshen granules inhibits dendritic cell glycolipid metabolism to alleviate renal fibrosis via PI3K-AKT-mTOR pathway

BackgroundQingshen exhibits anti-inflammatory and immunoregulation effects to renal damage. Dendritic cells (DCs) play a critical role in regulating the pathologic inflammatory environment in renal fibrosis (RF). PurposeTo investigate the immune modulation mechanism of qingshen granule (QSG) in RF, particularly focusing on the role of DCs. Methods/Study designAdenine-induced RF animal models were used to study the pharmacological effects of QSG and the immune cells differentiation and function. Glucose uptake, non-esterified fatty acids secretion, mitochondrial membrane potential (MMP) detection, and qPCR were used to explore the effect of QSG to glucose and lipid metabolism in DCs and T cells. The effect of QSG to PI3K-AKT-mTOR axis and the modulation of mTOR to PD-L1 were explored by co-culture experiments, co-immunoprecipitation and western blot assays. The interaction of DCs/CD8+T cells and renal tubular epithelial cells (RTECs) was investigated to demonstrate the direct action and/or the immune-mediated regulation of QSG to RF. The components of QSG in the serum were determined by HPLC. And the effect of active ingredients and formula to DCs and T cells was analyzed by cell experiments in vitro. ResultsQSG reduced nephritic histopathological damage and suppressed the release of proinflammatory cytokines in adenine-induced RF mice. Of note, QSG decreased the levels of CD86, MHC-II, and CCR7 on DCs, while, increased PD-L1 expression on DCs in RF. The results demonstrated that QSG promoted the maturation and inhibited the migration of DCs, and QSG decreased the antigen presenting of DCs to T cells. Additionally, QSG reduced the MMP and glucose/lipid utilization ratio in DCs. QSG also down-regulated the level of targeted metabolic genes included glucose transporter 1 (Glut1), sterol-regulatory element-binding protein 1 (Srebp1), acetyl-CoA carboxylase alpha (Acaca), phosphomevalonate kinase (Pmvk), and up-regulated sirtuin2 (Sirt2) in DCs. In terms of mechanism, QSG inhibited the metabolism-related PI3K-AKT-mTOR pathway, followed by regulating the interaction of mTOR with PD-L1 to enhance the membrane stability of PD-L1. Besides, HPLC analysis identified five active ingredients in QSG. The specific anti-inflammatory and immunosuppressive actions of these ingredients were found to be weaker than QSG as a whole. Finally, inhibiting DC function by QSG disrupted the communication among DCs, T cells, and RTECs. This disruption was associated with low expression of α-smooth muscle actin (α-SMA) and collagen type I (Col-I) in the kidney. ConclusionsQSG inhibits DC metabolism and function via the PI3K-AKT-mTOR pathway to alleviate RF. The study highlights the importance of the specific composition of the formula in targeting DC-mediated immune regulation.

Tumor Resection in Hepatic Carcinomas Restores Circulating T Regulatory Cells.

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection.

Understanding Iron-Doping Modulating Domain Orientation and Improving the Device Performance of Monolayer Molybdenum Disulfide.

Domain orientation modulation and controlled doping of two-dimensional (2D) transition-metal dichalcogenides (TMDCs) are two pivotal tasks for synthesizing wafer-scale single crystals and boosting device performances. However, realizing two such targets and uncovering internal physical mechanisms remain daunting challenges. We develop an accurate Fe doping strategy, which enables domain orientation control and electron mobility improvement of monolayer MoS2. By tuning of the Fe dopant dosages, parallel steps with different heights are formed, which induce edge-nucleation of unidirectionally aligned monolayer MoS2. In parallel, Fe doping induces the down shift of the conduction band minimum of monolayer MoS2 and matches well with the work function of an electrode, which reduces Schottky barrier height and delivers ultralow contact resistance (561 Ω μm) and excellent electron mobility (37.5 cm2 V-1 s-1). The modulation mechanism is clarified by combining theory calculations and electronic structure characterizations. This work hereby provides a new paradigm for synthesizing wafer-scale 2D TMDC single crystals and constructing high-performance devices.

Oral toxicity assessment and the mitigation of lung carcinogenesis by phytol and α-bisabolol combination treatment in swiss albino mice: insights into redox enzyme modulation and caspase-dependent cell death mechanisms.

This study examined the safety and potential anti-lung cancer effects of combinations of phytol and α-bisabolol in Swiss albino mice. Both acute and subacute toxicity assessments showed that the combination of phytol and α-bisabolol is safe, with no adverse effects observed at higher concentrations. Hematological, biochemical, and histopathological tests showed no signs of toxicity in the heart, lungs, liver, spleen, and kidneys. The LD50 was greater than 2000mg/kg, indicating a large safety margin. Histopathological analysis confirmed cancer induction in the B(a)P-induced group, which had significantly altered relative lung weights. Lung weight increased slightly pre and post-treatment, but histopathology showed normal alveolar epithelium. GSH and SOD levels increased significantly in B(a)P-exposed groups, indicating an adaptive antioxidant response. CAT levels increased significantly in the post-treatment group, demonstrating the role of combination of phytol and α-bisabolol in protecting against B(a)P-induced oxidative damage. Upregulation of Bax and downregulation of Bcl-2 caused a pro-apoptotic environment, suggesting a way to inhibit malignant cell survival. Modulation of caspase-3 and caspase-9 showed the complexity of carcinogen-induced apoptotic signaling. In conclusion, phytol and α-bisabolol were found to be safe and organ-protective, and demonstrated no acute or subacute toxicity. They modulate antioxidant defenses and apoptotic pathways, which may help prevent and treat lung cancer.

SPMs exert anti-inflammatory and pro-resolving effects through positive allosteric modulation of the prostaglandin EP4 receptor

Inflammation is a protective response to pathogens and injury. To be effective it needs to be resolved by endogenous mechanisms in order to avoid prolonged and excessive inflammation, which can become chronic. Specialized pro-resolving mediators (SPMs) are a group of lipids derived from omega-3 fatty acids, which can induce the resolution of inflammation. How SPMs exert their anti-inflammatory and pro-resolving effects is, however, not clear. Here, we show that SPMs such as protectins, maresins, and D-series resolvins function as biased positive allosteric modulators (PAM) of the prostaglandin E2 (PGE2) receptor EP4 through an intracellular binding site. They increase PGE2-induced Gs-mediated formation of cAMP and thereby promote anti-inflammatory signaling of EP4. In addition, SPMs endow the endogenous EP4 receptor on macrophages with the ability to couple to Gi-type G-proteins, which converts the EP4 receptor on macrophages from an anti-phagocytotic receptor to one increasing phagocytosis, a central mechanism of the pro-resolving activity of synthetic SPMs. In the absence of the EP4 receptor, SPMs lose their anti-inflammatory and pro-resolving activity in vitro and in vivo. Our findings reveal an unusual mechanism of allosteric receptor modulation by lipids and provide a mechanism by which synthetic SPMs exert pro-resolving and anti-inflammatory effects, which may facilitate approaches to treat inflammation.

Immune modulation and epigenetic therapies for enhanced outcome of treatment in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor expression. While traditional TNBC treatment primarily relies on systemic chemotherapy, epigenetic modification has an important role in immune evasion and tumor progression. Recent classifications of TNBC into “hot” and “cold” tumors, based on immune activity and mutation burden, have revealed that poor response to immune checkpoint inhibitors (ICIs) in these tumors is due to low tumor-infiltrating lymphocytes and the presence of immunosuppressive cells. Emerging treatments such as ICIs and poly(ADP-ribose) polymerase inhibitors offer promising alternatives. The tumor microenvironment (TME) shapes immune responses in TNBC, and a limited subset of patients has shown encouraging responses to ICIs in treating TNBC at both early and advanced stages. However, combination therapies face challenges, including medication interactions and side effects. Epigenetic modulators, such as histone deacetylase and DNA methyltransferase inhibitors, also show promise in reversing epigenetic changes by enhancing anti-tumor immunity in TNBC. The frequent expression of indoleamine 2,3-dioxygenase 1 (IDO1) in TNBC, which catalyzes the conversion of tryptophan to kynurenine, contributes to immune suppression in TNBC patients. High IDO1 levels impair the tumoricidal activity of natural killer cells and correlate with poor responses to anti-PD-L1 therapy, which can be improved using IDO1 inhibitors. Targeting myeloid-derived suppressor cells, regulatory T-cells, and tumor-associated macrophage, along with utilizing epigenetic mechanisms, show promise in modulating the immunosuppressive TME in TNBC. Combining these approaches with standard therapies, along with biomarker-guided patient selection, can enhance treatment efficacy. Clinical trials and preclinical models are essential for optimizing these strategies. This study emphasizes the importance of understanding the mechanisms of modulation, tumor-immune interactions, and the potential of epigenetic therapies in improving treatment outcomes in TNBC.