Biased Signaling Research Articles

Sodium MRI of the skin using a surface coil to investigate and reduce signal loss and bias.

The purpose was to improve sodium MRI of human skin using a surface coil and twisted projection imaging with smaller, reshaped voxels. Calf skin sodium images were acquired in 14 healthy adults using twisted projection imaging with short TE ˜ 0.1 ms, first with a volume coil and voxels (1.5 × 1.5 × 15 = 34 mm3) reflecting the widely adopted skin imaging protocol (VolPencil). A 5-cm-diameter surface coil then facilitated 5× smaller (0.8 × 0.8 × 10 = 6.4 mm3) voxels with similar signal to noise ratio (SNR) in the same 12-min scan time (SurfPencil). "Pencil-shaped" voxels were then replaced with "pancake-shaped" (0.4 × 4 × 4 = 6.4 mm3) voxels, matching the anatomy of pressed flat skin (SurfPancake). Surface coil B1 was investigated with the novel use of spin-3/2 simulation. Protocol modifications were tested for signal increase (reduced loss) and correlation with (bias by) skin thickness. Higher resolution SurfPencil yielded 44% ± 16% greater skin sodium image intensity than VolPencil, whereas SurfPancake yielded an additional 20% ± 9% (p < 1e-8), reflecting reduced signal loss. Over the 1.0 to 1.8 mm skin thickness across participants, sodium intensity significantly increased 56% ± 19% and 44% ± 12% for VolPencil and SurfPencil, respectively (p < 0.003), but not for SurfPancake, reflecting reduced bias. Imaging yielded skin sodium concentration of 34 ± 5 mM for SurfPancake. This is greater than the ˜20 mM measures from the widely adopted protocol, but simulation (matching experimental trends) identified a remaining 64% signal loss; compensation yields 95 ± 15 mM. Surface coil imaging and "pancake" voxel reshaping increased skin sodium intensity and reduced bias by skin thickness. Simulated loss compensation yields skin sodium concentration similar to that measured by atomic absorption spectroscopy.

Agonists of the nuclear receptor PPARγ can produce biased signaling.

Biased signaling and ligand bias, often termed functional selectivity or selective nuclear receptor modulation, have been reported for nuclear receptor partial agonists over the past 20 years. Whether signaling differences produced by partial agonists result from less intense modulation, off-target effects, or biased signaling remains unclear. A commonly postulated mechanism for biased signaling is coactivator favoritism, where agonists induce different coactivator recruitment profiles. We find that both GW1929 (full agonist) and MRL24 (partial agonist) favor recruitment of 100-300 residue regions from S-motif coactivators compared to a reference full agonist (rosiglitazone), yielding 95% bias value confidence intervals of 0.05-0.17 and 0.29-0.38 respectively. Calculations based on these data indicate that GW1929 and MRL24 would induce 30-60% higher S-motif coactivator occupancy at the receptor compared to rosiglitazone. We compare the transcriptional effects of these same three ligands on human adipocytes using RNA sequencing and exploratory KEGG pathway analysis. Only 50% (rosiglitazone) and 77% (GW1929) of all gene expression changes are shared between these full agonists after 3 hours of exposure. After 24 hours of exposure, 13/98 KEGG pathways appear more intensely modulated by rosiglitazone than GW1929 (e.g., 95% CI of bias in the regulation of lipolysis in adipocytes pathway is 0.03-0.09), despite similar signaling for the remaining 85 affected pathways. Similarly, rosiglitazone has an unusually large effect on several lipid metabolism-related pathways compared to the partial agonist MRL24. These data indicate that nuclear receptor full and partial agonists can induce biased signaling, likely through differences in coactivator recruitment. Significance Statement Many nuclear receptor partial agonists cause fewer adverse effects and similar efficacy compared to full agonists, potentially by inducing biased agonism. Our data support the idea that partial agonists, and a full agonist, of the nuclear receptor Peroxisome proliferator-activated receptor gamma (PPARγ) are biased agonists, causing different signaling by inducing PPARγ to favor different coactivators. These data indicate that biased agonism can occur in nuclear receptors and should be considered in efforts to develop improved nuclear receptor-targeted drugs.

Tumor-intrinsic role of ICAM-1 in driving metastatic progression of triple-negative breast cancer through direct interaction with EGFR

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

Cryogenic quantum computer control signal generation using high-electron-mobility transistors

Multiplexed local charge storage, close to quantum processors at cryogenic temperatures could generate a multitude of control signals, for electronics or qubits, in an efficient manner. Such cryogenic electronics require generating quasi-static control signals with small area footprint, low noise, high stability, low power dissipation and, ideally, in a multiplexed fashion to reduce the number of input/outputs. In this work, we integrate capacitors with cryogenic high-electron mobility transistor (HEMT) arrays and demonstrate quasi-static bias generation using gate pulses controlled in time and frequency domains. Multi-channel bias generation is also demonstrated. Operation at 4 K exhibits improved bias signal variability and greatly reduced subthreshold swing, reaching values of ~6 mV/decade. Due to the very low threshold voltage of 80 mV at 4 K and the steep subthreshold swing, these circuits can provide an advantage over the silicon-based complementary metal-oxide-semiconductor equivalents by allowing operation at significantly reduced drive bias in the low output voltage regime <1 V. Together with their high-speed operation, this makes HEMTs an attractive platform for future cryogenic signal generation electronics in quantum computers.

Ethanol drinking sex-dependently alters cortical IL-1β synaptic signaling and cognitive behavior in mice.

Individuals with alcohol use disorder (AUD) struggle with inhibitory control, decision making, and emotional processing. These cognitive symptoms reduce treatment adherence, worsen clinical outcomes, and promote relapse. Neuroimmune activation is a key factor in the pathophysiology of AUD, and targeting this modulatory system is less likely to produce unwanted side effects compared to directly targeting neurotransmitter dysfunction. Notably, the cytokine interleukin-1β (IL-1β) has been broadly associated with the cognitive symptoms of AUD, though the underlying mechanisms are not well understood. Here we investigated how chronic intermittent 24-hour access two bottle choice ethanol drinking affects medial prefrontal cortex (mPFC)-related cognitive function and IL-1 synaptic signaling in male and female C57BL/6J mice. In both sexes, ethanol drinking decreased reference memory and increased mPFC IL-1 receptor 1 (IL-1R1) mRNA levels. In neurons, IL-1β can activate either pro-inflammatory or neuroprotective intracellular pathways depending on the isoform of the accessory protein (IL-1RAcP) recruited to the IL-1R1 complex. Moreover, ethanol drinking sex-dependently shifted mPFC IL-1RAcP isoform gene expression and IL-1β regulation of mPFC GABA synapses, both of which may contribute to female mPFC resiliency and male mPFC susceptibility. This type of signaling bias has become a recent focus of rational drug development. Therefore, in addition to increasing our understanding of how IL-1β sex-dependently contributes to mPFC dysfunction in AUD, our current findings also support the development of a new class of pharmacotherapeutics based on biased IL-1 signaling.

Reversing Arrested Development: A New Method to Address Halo Assembly Bias

Abstract Halo assembly bias is a phenomenon whereby the clustering of dark matter halos is dependent on halo properties, such as age, at fixed mass. Understanding the origin of assembly bias is important for interpreting the clustering of galaxies and constraining cosmological models. One proposed explanation for the origin of assembly bias is the truncation of mass accretion in low-mass halos in the presence of more massive halos, called ‘arrested development.’ Halos undergoing arrested development would have older measured ages and exhibit stronger clustering than equal mass halos that have not undergone arrested development. We propose a new method to test the validity of this explanation for assembly bias, and correct for it in cosmological N-body simulations. The method is based on the idea that the early mass accretion history of a halo, before arrested development takes effect, can be used to predict the late-time evolution of the halo in the absence of arrested development. We implement this idea by fitting a model to the early portion of halo accretion histories and extrapolating to late times. We then calculate ‘corrected’ masses and ages for halos based on this extrapolation and investigate how this impacts the assembly bias signal. We find that correcting for arrested development this way leads to a factor of two reduction in the strength of the assembly bias signal across a range of low halo masses. This result provides new evidence that arrested development is a cause of assembly bias and validates our approach to mitigating the effect.

Anti-machine-learning-attack strong PUF design based on multi-path delay selection strategy

Physical unclonable functions (PUF) have significant potential for application in information security. However, strong PUFs are vulnerable to machine learning (ML) modeling attacks, which severely limit their application in device authentication. Despite a variety of resistance techniques, strong PUFs suffer from hardware cost and stability deficiencies. This study proposes an anti-machine-learning-attack strong PUF based on a multi-path delay selection strategy through research on the entropy source of a strong PUF and the delay signal selection mechanism. First, we constructed a deviation source circuit based on multiplexers to increase the diversity of the delay signal transmission paths. Second, we constructed a delay selection circuit based on the logic gates. This circuit dynamically selects the delay signals with the same transmission path in the deviation source using AND and OR gates. Subsequently, the deviation source and delay selection circuits were utilized to construct the delay module, and the interconnection module was inserted between the delay modules to achieve alternating appearances of different types of logic gates along the delay path. Finally, RS flip-flops were employed to make decisions on the bias signals with the same delay path, and the final response was output through an XOR operation. The proposed PUF was implemented on a Xilinx Artix-7 FPGA, and the prediction accuracy of the four typical ML models was below 59 % (with 500,000 challenge-response pairs as the training set). Moreover, the proposed PUF structure is scalable and exhibits better performance in terms of hardware cost and stability than existing classic structures.

Biased activation of the vasopressin V2 receptor probed by molecular dynamics simulations, NMR and pharmacological studies.

G protein-coupled receptors (GPCRs) control critical cell signaling. Their response to extracellular stimuli involves conformational changes to convey signals to intracellular effectors, among which the most important are G proteins and β-arrestins (βArrs). Biased activation of one pathway is a field of intense research in GPCR pharmacology. Combining NMR, site-directed mutagenesis, molecular pharmacology, and molecular dynamics (MD) simulations, we studied the conformational diversity of the vasopressin V2 receptor (V2R) bound to different types of ligands: the antagonist Tolvaptan, the endogenous unbiased agonist arginine-vasopressin, and MCF14, a partial Gs protein-biased agonist. A double-labeling NMR scheme was developed to study the receptor conformational changes and ligand binding: V2R was subjected to lysine 13CH3 methylation for complementary NMR studies, whereas the agonists were tagged with a paramagnetic probe. Paramagnetic relaxation enhancements and site-directed mutagenesis validated the ligand binding modes in the MD simulations. We found that the bias for the Gs protein over the βArr pathway involves interactions between the conserved NPxxY motif in the transmembrane helix 7 (TM7) and TM3, compacting helix 8 (H8) toward TM1 and likely inhibiting βArr signaling. A similar mechanism was elicited for the pathogenic mutation I130N, which constitutively activates the Gs proteins without concomitant βArr recruitment. The findings suggest common patterns of biased signaling in class A GPCRs, as well as a rationale for the design of G protein-biased V2R agonists.

Global Trends in Oliceridine (TRV130) Research from 2013 to 2024: A Bibliometrics and Knowledge Graph Analysis.

The adverse effects and drug abuse issues associated with opioid drugs have made finding a safe and effective alternative a focus of research. Oliceridine has attracted attention for its lower adverse reactions, such as respiratory depression and gastrointestinal issues, compared to traditional opioids, and is considered a promising candidate for addressing the current limitations in opioid therapy. This article explored the knowledge structure of oliceridine through bibliometric analysis, highlighting its clinical applications in managing acute pain and its mechanisms that may reduce addiction risk. Our bibliometric analysis highlighted hotspots and trends in oliceridine research, guiding future studies on its safety and efficacy in pain management. This study utilized the Web of Science Core Collection database to search for articles related to oliceridine from 2013 to 2024. Systematic analysis was conducted on publication, country, institution, author, journal, references, and keywords. The software Citespace, Vosviewer, and Bibliometrix were employed to visualize bibliometric analysis. From 2013 to 2024, 159 articles on oliceridine were published in 98 journals by 158 institutions from 28 countries. The United States has rapidly developed in this field, providing significant momentum. Keyword clustering analysis revealed that research on oliceridine primarily focused on exploring its molecular and pharmacological mechanisms and conducting clinical studies to evaluate its efficacy and safety in pain management. Analyses of the strongest citation bursts with references and keywords indicated that protein-biased ligands and oliceridine were hotspots. The emergence of divergent views regarding oliceridine's biased agonism will lead to future hotspots focusing on the underlying mechanisms of biased signaling by G protein-coupled receptors and drug design. Bibliometric analysis provides insights into the current hotspots and emerging areas of oliceridine, which can guide future research. The widespread attention and clinical application of oliceridine lay a solid foundation for further drug development and clinical trials.

Galaxy Assembly Bias in the Stellar-to-halo Mass Relation for Red Central Galaxies from SDSS

We report evidence of galaxy assembly bias—the correlation between galaxy properties and biased secondary halo properties at fixed halo mass (M H)—in the stellar-to-halo mass relation for red central galaxies from the Sloan Digital Sky Survey. In the M H = 1011.5–1013.5 h −1 M ⊙ range, central galaxy stellar mass (M *) is correlated with the number density of galaxies within 10 h −1 Mpc (δ 10), a common proxy for halo formation time. This galaxy assembly bias signal is also present when M H, M *, and δ 10 are substituted with group luminosity, galaxy luminosity, and metrics of the large-scale density field. To associate differences in δ 10 with variations in halo formation time, we fitted a model that accounts for (1) errors in the M H measured by the J. L. Tinker group catalog and (2) the level of correlation between halo formation time and M * at fixed M H. Fitting of this model yields that (1) errors in M H are ∼0.15 dex and (2) halo formation time and M * are strongly correlated (Spearman’s rank correlation coefficient ∼0.85). At fixed M H, variations of ∼0.4 dex in M * are associated with ∼1–3 Gyr variations in halo formation time and galaxy formation time (from stellar population fitting). These results are indicative that halo properties other than M H can impact central galaxy assembly.

Research on Spatial Localization Method of Magnetic Nanoparticle Samples Based on Second Harmonic Waves

Existing magnetic tracer detection systems primarily rely on fundamental wave signal acquisition using non-differential sensor configurations. These sensors are highly susceptible to external interference and lack tomographic localization capabilities, hindering their clinical application. To address these limitations, this paper presents a novel method for achieving the deep spatial localization of tracers. The method exploits second harmonic signal detection at non-zero field points. By considering the combined nonlinear characteristics of the coil’s axial spatial magnetic field distribution and the Langevin function, a correlation model linking the signal peak and bias field is established. This model enables the determination of the tracer’s precise spatial location. Building on this framework, a handheld device for localizing magnetic nanoparticle tracers was developed. The device harnesses the second harmonic response generated by coupling an AC excitation field with a DC bias field. Our findings demonstrate that under conditions of reduced coil turns and weak excitation fields, the DC bias field exhibits exclusive dependence on the axial distance of the detection point, independent of particle concentration. This implies that the saturated DC bias field corresponding to the second harmonic signal can be used to determine the magnetic nanoparticle sample detection depth. The experimental results validated the method’s high accuracy, with axial detection distance and concentration reduction errors of only 4.8% and 4.1%, respectively. This research paves the way for handheld probes capable of tomographic tracer detection, offering a novel approach for advancing magnetically sensitive biomedical detection technologies.

An incremental permeability detection method for yield strength of ferromagnetic materials based on permanent magnet excitation

ABSTRACT In this paper, in order to meet the engineering requirements of mechanical properties detection of materials with low power consumption, a novel incremental permeability detection system based on permanent magnet excitation is proposed to reduce system power consumption. Initially, a new incremental permeability sensor was designed to extract magnetic incremental permeability (MIP) signal. Through finite element simulation, experimental parameters were optimised, and a rational arrangement of double permanent magnets was devised to furnish an optimally strong AC bias field intensity. Subsequently, a practical detection platform was assembled to extract electromagnetic signal features. From the perspective of domain wall displacement, a characteristic value θ was proposed to predict the yield strength, with experimental results yielding a relative error of less than ±10%. These experiments have validated the capability of permanent magnet-type MIP to enable quantitative detection of the yield strength in ferromagnetic materials.

Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound

Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR’s structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.

Comparative analysis of formyl peptide receptor 1 and formyl peptide receptor 2 reveals shared and preserved signalling profiles.

The pattern recognition receptors, formyl peptide receptors, FPR1 and FPR2, are G protein-coupled receptors that recognize many different pathogen- and host-derived ligands. While FPR1 conveys pro-inflammatory signals, FPR2 is linked with pro-resolving outcomes. To analyse how the two very similar FPRs exert opposite effects in modulating inflammatory responses despite their high homology, a shared expression profile on immune cells and an overlapping ligand repertoire, we questioned whether the signalling profile differs between these two receptors. We deduced EC50 and Emax values for synthetic, pathogen-derived and host-derived peptide agonists for both FPR1 and FPR2 and analysed them within the framework of biased signalling. We furthermore investigated whether FPR isoform-specific agonists affect the ex vivo lifespan of human neutrophils. The FPRs share a core signature across signalling pathways. Whereas the synthetic WKYMVm and formylated peptides acted as potent agonists at FPR1, and at FPR2, only WKYMVm was a full agonist. Natural FPR2 agonists, irrespective of N-terminal formylation, displayed lower activity ratios, suggesting an underutilized signalling potential of this receptor. FPR2 agonism did not counteract LPS-induced neutrophil survival, indicating that FPR2 activation per se is not linked with a pro-resolving function. Activation of FPR1 and FPR2 by a representative agonist panel revealed a lack of a receptor-specific signalling texture, challenging assumptions about distinct inflammatory profiles linked to specific receptor isoforms, signalling patterns or agonist classes. These conclusions are restricted to the specific agonists and signalling pathways examined.

Balanced air-biased detection of terahertz waveforms.

A novel, to the best of our knowledge, balanced air-biased coherent detection scheme for capturing ultrabroadband terahertz (THz) waveforms is implemented. The balanced detection scheme allows for coherent detection at the full repetition rate of the laser system without requiring bias modulation, signal generators, or lock-in amplifiers while doubling the dynamic range and quadrupling the signal-to-noise ratio compared to conventional air-biased coherent detection. These advantages are achieved by rotating the bias electrodes by 90° relative to the conventional scheme. With a 1 kHz driving laser, the scheme enables sub-second, high-fidelity waveform acquisition with a continuously moving delay stage, demonstrated by collecting 200 waveforms in 100 s. The balanced detection scheme paves the way for much faster and higher quality 2D ultrabroadband terahertz spectroscopy.

Conorphin-66 produces peripherally restricted antinociception via the kappa-opioid receptor with limited side effects

With the current unmet demand for effective pain relief, analgesics without major central adverse effects are highly appealing, such as peripherally restricted kappa-opioid receptor (KOR) agonists. In this study, Conorphin-66, an analog of the selective KOR peptide agonist Conorphin T, was pharmacologically characterized in a series of experiments, with CR845 serving as the reference compound. Firstly, in vitro functional assay indicated that Conorphin-66 selectively activates KOR and exhibits weak β-arrestin2 signaling bias (−1.54 versus −4.35 for CR845). Additionally, subcutaneous Conorphin-66 produced potent antinociception in mouse pain models with ED50 values ranged from 0.02 to 3.28 μmol/kg, including tail-flick test, post-operative pain, formalin pain, and acetic acid-induced visceral pain. Similarly, CR845 exert potent antinociception in mouse pain models ranged from 0.15 to 1.47 μmol/kg. Notably, antagonism studies revealed that the analgesic effects of Conorphin-66 were mainly mediated by the peripheral KOR. Furthermore, Conorphin-66 produced non-tolerance-forming antinociception over 8 days. Unlike CR845, subcutaneous Conorphin-66 did not promote the sedation, anxiogenic effects, depressive-like effects, but did exhibit diuretic activity. Further study showed that Conorphin-66 does not have apparent antipruritic effects in an acute itch model. Overall, Conorphin-66 emerges as a novel peripherally restricted KOR agonist that produced potent antinociception with reduced side effects.

Implications of β-Arrestin biased signaling by angiotensin II type 1 receptor for cardiovascular drug discovery and therapeutics

Angiotensin II receptors, Type 1 (AT1R) and Type 2 (AT2R) are 7TM receptors that play critical roles in both the physiological and pathophysiological regulation of the cardiovascular system. While AT1R blockers (ARBs) have proven beneficial in managing cardiac, vascular and renal maladies they cannot completely halt and reverse the progression of pathologies. Numerous experimental and animal studies have demonstrated that β-arrestin biased AT1R-ligands (such as SII-AngII, S1I8, TRV023, and TRV027) offer cardiovascular benefits by blocking the G protein signaling while retaining the β-arrestin signaling. However, these ligands failed to show improvement in heart-failure outcome over the placebo in a phase IIb clinical trial. One major limitation of current β-arrestin biased AT1R-ligands is that they are peptides with short half-lives, limiting their long-term efficacy in patients. Additionally, β-arrestin biased AT1R-ligand peptides, may inadvertently block AT2R, a promiscuous receptor, potentially negating its beneficial effects in post-myocardial infarction (MI) patients. Therefore, developing a small molecule β-arrestin biased AT1R-ligand with a longer half-life and specificity to AT1R could be more effective in treating heart failure. This approach has the potential to revolutionize the treatment of cardiovascular diseases by offering more sustained and targeted therapeutic effects.

Progress on the development of Class A GPCR-biased ligands.

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.

An integrated multichannel system for air-coupled CMUT array imaging and guided wave detection applications

Abstract Capacitive micromachined ultrasonic transducers (CMUTs) made by MEMS process have become a new choice for air-coupled ultrasonic transducers due to their high sensitivity, low acoustic impedance and easy arraying. At present, in the air coupling application of CMUT transducer, due to the weak signal strength of single element, the CMUT array usually works in a whole piece, limiting the advantage of the array. Therefore, a multi-channel air-coupled CMUT imaging system with high-voltage DC bias and low-noise high-gain current signal amplification is designed to realize the electronic scanning of our CMUT arrays. The imaging system has 16 transmit and receive channels, and each channel consists of pulse transmitting circuit, AC/DC coupling circuit, impedance matching circuit, low-noise transimpedance amplification circuit, controllable gain amplification circuit and AD circuit. The imaging chain and element control method of our CMUT array were developed to realize the electronic scanning imaging of air-coupled ultrasound. The feasibility of the system for non-destructive testing was also verified via the Lamb wave detection in a metal plate.…

Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell

The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ Tcell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ Tcell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.