Additional Signal Research Articles

Self-powered multifunctional platform based on dual-photoelectrode for dual-mode detection and inactivation of Salmonella enteritidis

Self-powered photoelectrochemical (PEC) sensing is a novel sensing modality. The introduction of dual-mode sensing and photoelectrocatalysis in a self-powered system enables both detection and sterilization purposes. To this end, herein, a self-powered multifunctional platform for the photoelectrochemical-fluorescence (PEC-FL) detection and in-situ inactivation of Salmonella enteritidis (SE) was constructed. The platform utilized Bi4NbO8Cl/V2CTx/FTO as a photoanode and CuInS2/FTO as a photocathode and incubated quantum dot (QDs) signaling probes on the surface of the photocathode. During detection, the system drives the transfer of photogenerated electrons between the dual photoelectrodes through the Fermi energy level difference. The photoanode amplifies the photoelectric signal, while the photocathode is solely dedicated to the immune recognition process. QDs provide an additional fluorescence signal to the system. Under optimal experimental conditions, the multifunctional platform achieves detection limits of 3.2 and 5.3 CFU/mL in PEC and FL modes respectively, with a detection range of 2.91 × 102 to 2.91 × 108 CFU/mL. With the application of an external bias voltage, it further promotes electron transfer between the dual photoelectrodes, inhibits the recombination of photogenerated electrons and holes. It generates a significant amount of superoxide radicals (·O2−) in the cathodic region, resulting in strong sterilization efficiency (99%). The constructed self-powered multifunctional platform exhibits high sensitivity and sterilization efficiency, it provides a feasible and effective strategy to enhance the comprehensive capability of self-powered sensors.

Wild horse optimization algorithm implementation in 7-level packed U-cell multilevel inverter to mitigate total harmonic distortion

Introduction. Multilevel inverters (MLIs) are a popular industrial and, more especially, renewable energy application solution. This is because of its appetite for filters, low distortion class, and capacity to provide a multilayer output voltage that resembles a pure sine waveform. The novelty is in applying the wild horse optimization algorithm (WHOA) to adjust the sinusoidal pulse width modulation (SPWM) technique by producing the optimal reference signal parameters in a new multilevel inverter architecture known as the packed U-cell multilevel inverter (PUC-MLI). Purpose. This study helps with the idea of new inverter architecture and a modified pulse width modulation (MPWM) method to make the multilevel inverter smaller, cheaper, and with less total harmonic distortion (THD). Methods. We use the proposed approach to control a 7-level, single-phase PUC-MLI. The WHOA is used to discover the optimal parameters of the additional reference sine signal after being compared with SPWM to evaluate its performance in harmonic reduction. The simulation’s outcome was validated by building a PUC-MLI prototype. Results. Experimental results and simulations validate the effectiveness of the suggested approach. The WHOA-improved MPWM approach achieves a significant reduction in THD on the PUC-MLI output voltage, as indicated by the results. Practical value. THD in MLI output voltage will be reduced without spending any cost. The suggested solution works with many MLI topologies with varying output voltage levels. References 20, tables 6, figures 12.

Magnetic properties of polycrystalline bulk crystals of MnGeP2

Room temperature ferromagnetism observed in polycrystalline MnGeP2 bulk samples was investigated by different experimental techniques. The magnetization measurements show a high temperature ferromagnetic phase with a critical temperature TC = 294.0 K and a low temperature magnetic phase transition at TN = 40.5 K. As these parameters (TC,TN) correspond to those of MnP, a ferromagnetic half-metal, whose composition of the samples was further characterized by x-ray diffraction and Rutherford backscattering measurements. They confirmed the presence of orthorhombic MnP precipitates. Electron paramagnetic resonance (EPR) and ferromagnetic resonance (FMR) measurements in the temperature range of T = 4 K to T = 380 K confirm the attribution of the magnetic phase to MnP and show no additional EPR or FMR signal associated with MnGeP2. We conclude that the magnetic properties of the polycrystalline MnGeP2 bulk samples grown by the horizontal gradient freeze technique are dominated by MnP inclusions and that phase pure chalcopyrite MnGeP2 is not ferromagnetic in contrary to previous reports.

A Chimeric IL-7Rα/IL-2Rβ Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R β-chain (IL-24β) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rβ under the control of the endogenous IL-7Rα promoter. Notably, this 72R receptor induced higher levels of STAT5 and Akt phosphorylation in T cells. In the periphery of 72R mice, the number of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was increased, whereas early T cell progenitors and double-negative 2 thymocytes were reduced in the thymus. In addition, cell proliferation and Notch signaling were impaired in the early thymocytes of 72R mice, leading to their differentiation into thymic B cells. Interestingly, ILC2s were increased in the thymus of 72R mice. Early T cell progenitors from 72R mice, but not from wild-type mice, differentiated into NK cells and ILC2-like cells when cocultured with a thymic stromal cell line. Thus, this study indicates that the chimeric 72R receptor transduces more robust signals than the authentic IL-7Rα, thereby inducing the alternative differentiation of T cell progenitors into other cell lineages. This suggests that cytokine receptors may provide instructive signals for cell fate decisions.

Report on the 12th international workshop on the CCN family of genes, Oslo, June 20-23, 2024.

The 12th international workshop on the CCN family of genes took place at the Scandic Holmenkollen Park Hotel in Oslo, Norway from June 20-23, 2024. In 2024, it was the second time, following the Nice meeting in 2022, that the scientific topics were expanded to include additional cellular signaling and communication pathways of interest to the CCN Society members, as suggested by Bernard Perbal in 2019. The 12th international CCN workshop, organized by Håvard Attramadal and Vivi T. Monsen, along with co-organizers Bernard and Annick Perbal, was given the subtitle "Cell-matrix Communication and Functions in Health and Disease" to encompass the broader scope of this meeting. The five scientific sessions covered various topics: Extracellular Matrix Proteins in Cell Communication and Signaling (Chaired by Brahim Chaqour and Vivi T. Monsen), Vascular Development and Pathophysiology (Chaired by Lester F. Lau and Håvard Attramadal), Mechanisms of Diseases (Chaired by George Bou-Gharios and Satoshi Kubota), Tissue Development and Homeostasis (Chaired by Blandine Poulet and Bernard Perbal), and Mechanisms of Disease: Cancer and the Matrix (Chaired by Stephen M. Twigg and Raymond B. Birge). The 2024 ICCNS Award was presented to Katia Scotlandi during the last session (Chaired by Bernard Perbal) before Håvard Attramadal presented the conclusion of the workshop.

PA-Net: Trustworthy weakly supervised point cloud semantic segmentation with primary–auxiliary structure

Weakly supervised point cloud segmentation is a hot research topic with significant implications for practical applications such as autonomous driving. However, existing weakly supervised approaches primarily focus on improving prediction results while neglecting the reliability of the inference outcomes. To address this issue, this paper proposes a primary–auxiliary network PA-Net for point cloud segmentation and uncertainty estimation. PA-Net achieves excellent segmentation results and enables effective uncertainty assessment. Specifically, we first train PA-Net on sparsely annotated point cloud data, which allows our network to capture multi-scale information of labeled points and provide additional supervisory signals. Subsequently, we utilize the trained model for inference. We mainly conducted experiments on the indoor point cloud dataset S3DIS in a 1% labeled setting. PA-Net achieved a mean Intersection over Union (mIoU) of 64.5%, which surpasses most weakly-supervised methods. In particular, it exceeded PSD by 3.5% mIoU and SQN by 0.8% mIoU. Similarly, on the outdoor dataset Toronto3D, PA-Net also outperformed most weakly supervised methods. With only 0.01% labeling, it surpassed PSD by 11.99% mIoU and SQN by 20.34% mIoU. Lastly, to validate the effectiveness of uncertainty estimation, we visualized scene uncertainty, thereby demonstrating the practicality of our uncertainty estimation approach. Code will be made publicly available at https://github.com/NiuYingchun/PA-Net.

Output Regularization With Cluster-Based Soft Targets.

While supervised learning of over-parameterized neural networks achieved state-of-the-art performance in image classification, it tends to over-fit the labeled training samples to give inferior generalization ability. Output regularization deals with over-fitting by using soft targets as additional training signals. Although clustering is one of the most fundamental data analysis tools for discovering general-purpose and data-driven structures, it has been ignored in existing output regularization approaches. In this article, we leverage this underlying structural information by proposing Cluster-based soft targets for Output Regularization (CluOReg). This approach provides a unified way for simultaneous clustering in embedding space and neural classifier training with cluster-based soft targets via output regularization. By explicitly calculating a class relationship matrix in the cluster space, we obtain classwise soft targets shared by all samples in each class. Results of image classification experiments under various settings on a number of benchmark datasets are provided. Without resorting to external models or designed data augmentation, we get consistent and significant reductions in classification error compared with other approaches, demonstrating that cluster-based soft targets effectively complement the ground-truth label.

Preference Signaling in the Radiology Residency Match: National Survey of Applicants

ObjectiveTwo-tiered preference signaling has been implemented in the radiology residency application system to reduce congestion in the setting of high-volume applications. Signals are an indicator of strong interest that an applicant can transmit to a limited number of programs. This study assessed the impact of program signaling on interview invitations, how applicants strategically used signals based on their application’s competitiveness, and applicants’ attitudes toward the current signaling system. MethodsA survey was sent to radiology residency applicants registered with TheRadRoom during the 2024 application cycle. We queried the applicants’ background, applications, signal distribution, and interview outcome depending on the type of signal sent. We also asked whether respondents received an interview invitation from a hypothetical “comparator nonsignaled program” if they had one additional signal to use. Group differences were assessed using nonparametric Wilcoxon signed rank test. ResultsA total of 202 applicants completed the survey (28% response rate). Most applied to diagnostic radiology (81%). Nearly all respondents used all six gold (98%) and six silver (96.5%) signals. Interview invitation rates were significantly higher for signaled programs (59.8% ± 27.4%) than nonsignaled (8.5% ± 8.5%); the invitation rate at the comparator nonsignaled programs was 37%. Gold-signaled programs had significantly higher interview rates (67.8% ± 29.3) than silver (51.8% ± 31.3%). Respondents used 49.2% (±21.7%) of their signals for “likely to match” programs, 33.1% (±20.9%) for “aspirational” programs, and 17.6% (±15.8%) for “safety” programs. Most respondents (146; 76%) supported continuing the signaling system for future cycles. ConclusionSignaling programs significantly enhanced interview invitation rates, with gold signals being more effective than silver. The applicants used about six total signals for “likely-to-match” programs, two for “aspirational” programs, and about four for “safety” programs.

Neural adaptive performance guaranteed formation control for USVs with event-triggered quantized inputs

ABSTRACT This study presents an adaptive fault-tolerant performance guaranteed formation control strategy with event-triggered quantised inputs (EDQI) for unmanned surface vessels (USVs) in the presence of model uncertainties and actuator faults. Firstly, a prescribed performance formation guidance control law is proposed to allow formation tracking errors to evolve within the performance envelope and convergence to prescribed steady regions at an appointed time. Then, minimal-parameter-learning-based neural networks (MLP-NN) are used to tackle model uncertainties. To reduce the frequency of actuator updates and the communication burden on the channel, a dynamic memory event-triggered quantised input strategy is investigated. In addition, adaptive estimators and auxiliary design signals are built to compensate for the effects caused by input quantisation and actuator faults. It is proved that all closed-loop signals are bounded and formation errors can converge to the prescribed region at an appointed time. Finally, the effectiveness of the proposed controllers is verified by numerical simulations.

High energy resolution CsPbBr3 alpha particle detector with a full-customized readout application specific integrated circuit

α particles must be monitored to be managed as radioactive diagnostic agents or nuclear activity indicators. The new generation of perovskite detectors suffer from limited energy resolution, which affects spectroscopy and imaging applications. Here, we report that the solution-grown CsPbBr3 crystal exhibits a low and stable dark current (34.6 nA·cm−2 at 200 V) by thinning the as-grown crystal to decrease the high concentration CsPb2Br5 phase near the surface. The introduction of the Schottky electrode for the CsPbBr3 detector further reduces the dark current and improves the high-temperature stability. An energy resolution of 6.9% is achieved with the commercial electronic system, while the effects of air scattering and absorption are investigated. Moreover, 1.1% energy resolution is recognized by a full-customized readout application-specific integrated circuit without any additional signal processing, which matches well with the given parameters of the CsPbBr3 detector by reducing the parasitic capacitance and electronic noise.

Thiophene-based modified graphite electrode for the voltammetric detection of 2-aminoindane in oral fluid

New psychoactive substances, including 2-aminoindane, pose significant health risks due to their availability and structural similarity to amphetamines. Current detection methods are limited by lengthy analysis times and complex sample preparation. To address this, we present the first voltammetric determination of 2-aminoindane in oral fluid using a graphite electrode modified with a methoxyphenylthiophene-based layer. The electrochemically deposited layer was characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and both infrared and Raman spectroscopies. After the electropolymerization of methoxyphenylthiophene, the electrode was homogeneously covered with shorter oligomers of the substituted polythiophene. Cyclic and square-wave voltammetry were used to gain insight into the interaction between the modified electrode and 2-aminoindane. The modification of the electrode surface enables to record the oxidation of the primary amino group at 0.85 V, with an additional signal assigned to specific interactions being observed at 1.33 V. Determination of a 1.0 × 10–4 M 2-aminoindane concentration in oral fluids was possible, with a recovery ranging from 98 to 100%.Graphical abstract

Morphological Changes to Fruit Development Induced by GA3 Application in Sweet Cherry (Prunus avium L.).

Cherry (Prunus avium) fruits are important sources of vitamins, minerals, and nutrients in the human diet; however, they contain a large stone, making them inconvenient to eat 'on the move' and process. The exogenous application of gibberellic acid (GA3) can induce parthenocarpy in a variety of fruits during development. Here, we showed that the application of GA3 to sweet cherry unpollinated pistils acted as a trigger for fruit set and permitted the normal formation of fruit up to a period of twenty-eight days, indicating that gibberellins are involved in the activation of the cell cycle in the ovary wall cells, leading to fruit initiation. However, after this period, fruit development ceased and developing fruit began to be excised from the branch by 35 days post treatment. This work also showed that additional signals are required for the continued development of fully mature parthenocarpic fruit in sweet cherry.

Considering the incidence rate of RR Lyrae stars with non-radial modes

Over recent years, additional low-amplitude non-radial modes have been detected in many first-overtone RR Lyrae stars. These non-radial modes form a characteristic period ratio with the dominant first overtone of around 0.61. The incidence rate of this phenomenon varies from population to population. It is also strongly dependent on the quality of the analyzed data. Current models aimed at explaining these additional signals involve non-radial modes of degrees of 8 and 9. Using synthetic horizontal branch populations, we investigate the incidence rate of first-overtone RR Lyrae stars with non-radial modes, depending on the population properties, namely, ages and metallicities. We compare our results with the observed results for globular clusters and the vast collection of field first-overtone RR Lyrae stars to test the model predictions. We used synthetic horizontal branches combined with pulsation models to predict how the incidence rate would depend on the age and metallicity of the population. To test whether the results based on synthetic horizontal branches are realistic, we compared them to incidence rates observed by TESS in first-overtone field RR Lyrae stars, using photometric metallicity values from a newly established calibration for TESS. The analysis of synthetic horizontal branches indicates that the incidence rate decreases with decreasing metallicity. We inferred the photometric metallicity for RR Lyrae stars observed by TESS and showed that the theoretical predictions are in agreement with the observations. Using the same method, we also concluded that the metallicity distribution of RR Lyrae stars showing an additional mode with a period-ratio around $0.68$ appears to be different from that of 1) all first-overtone stars and 2) those showing additional non-radial modes.

Tumor necrosis factor regulates leukocyte recruitment but not bacterial persistence during Staphylococcus aureus craniotomy infection

BackgroundCraniotomy is a common neurosurgery used to treat intracranial pathologies. Nearly 5% of the 14 million craniotomies performed worldwide each year become infected, most often with Staphylococcus aureus (S. aureus), which forms a biofilm on the surface of the resected bone segment to establish a chronic infection that is recalcitrant to antibiotics and immune-mediated clearance. Tumor necrosis factor (TNF), a prototypical proinflammatory cytokine, has been implicated in generating protective immunity to various infections. Although TNF is elevated during S. aureus craniotomy infection, its functional importance in regulating disease pathogenesis has not been explored.MethodsA mouse model of S. aureus craniotomy infection was used to investigate the functional importance of TNF signaling using TNF, TNFR1, and TNFR2 knockout (KO) mice by quantifying bacterial burden, immune infiltrates, inflammatory mediators, and transcriptional changes by RNA-seq. Complementary experiments examined neutrophil extracellular trap formation, leukocyte apoptosis, phagocytosis, and bactericidal activity.ResultsTNF transiently regulated neutrophil and granulocytic myeloid-derived suppressor cell recruitment to the brain, subcutaneous galea, and bone flap as evident by significant reductions in both cell types between days 7 to 14 post-infection coinciding with significant decreases in several chemokines, which recovered to wild type levels by day 28. Despite these defects, bacterial burdens were similar in TNF KO and WT mice. RNA-seq revealed enhanced lymphotoxin-α (Lta) expression in TNF KO granulocytes. Since both TNF and LTα signal through TNFR1 and TNFR2, KO mice for each receptor were examined to assess potential redundancy; however, neither strain had any impact on S. aureus burden. In vitro studies revealed that TNF loss selectively altered macrophage responses to S. aureus since TNF KO macrophages displayed significant reductions in phagocytosis, apoptosis, IL-6 production, and bactericidal activity in response to live S. aureus, whereas granulocytes were not affected.ConclusionThese findings implicate TNF in modulating granulocyte recruitment during acute craniotomy infection via secondary effects on chemokine production and identify macrophages as a key cellular target of TNF action. However, the lack of changes in bacterial burden in TNF KO animals suggests the involvement of additional signals that dictate S. aureus pathogenesis during craniotomy infection.

Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines

BackgroundMetformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation.MethodsWe performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines.ResultsWe shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved.ConclusionsThese results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.Graphical

Cellular senescence mediates retinal ganglion cell survival regulation post-optic nerve crush injury.

Traumatic optic neuropathy refers to optic nerve (ON) injury by trauma, including explosion and traffic accident. Retinal ganglion cell (RGC) death is the critical pathological cause of irreversible visual impairment and blindness in ON injury. We previously investigated the patterns of 11 modes of cell death in mouse retina post-ON injury. Here we aimed to identify additional signalling pathways regulating RGC survival in rodents post-ON injury. RNA sequencing analysis identified the upregulation of inflammation and cellular senescence-related genes in retina post-ON injury, which were confirmed by immunoblotting and immunofluorescence analyses. Increased expression of senescence-associated β-galactosidase (SA-βgal) in RGCs and activation of microglia were also found. Transforming growth factor-β receptor type II inhibitor (LY2109761) treatment suppressed p15Ink4b and p21Cip1 protein and SA-βgal expression and promoted RGC survival post-ON injury with decreasing the expression of cell death markers in retina. Consistently, senolytics (dasatinib and quercetin) treatments can promote RGC survival and alleviate the reduction of ganglion cell complex thickness and pattern electroretinography activity post-ON injury with reducing SA-βgal, p15Ink4b, p21Cip1, microglial activation and cell death marker expression. In summary, this study revealed the activation of cellular senescence in rodent retina post-ON injury and contribute to RGC survival regulation. Targeting cellular senescence can promote RGC survival after ON injury, suggesting a potential treatment strategy for traumatic optic neuropathy.

Spatial entropy as an inductive bias for vision transformers

Recent work on Vision Transformers (VTs) showed that introducing a local inductive bias in the VT architecture helps reducing the number of samples necessary for training. However, the architecture modifications lead to a loss of generality of the Transformer backbone, partially contradicting the push towards the development of uniform architectures, shared, e.g., by both the Computer Vision and the Natural Language Processing areas. In this work, we propose a different and complementary direction, in which a local bias is introduced using an auxiliary self-supervised task, performed jointly with standard supervised training. Specifically, we exploit the observation that the attention maps of VTs, when trained with self-supervision, can contain a semantic segmentation structure which does not spontaneously emerge when training is supervised. Thus, we explicitly encourage the emergence of this spatial clustering as a form of training regularization. In more detail, we exploit the assumption that, in a given image, objects usually correspond to few connected regions, and we propose a spatial formulation of the information entropy to quantify this object-based inductive bias. By minimizing the proposed spatial entropy, we include an additional self-supervised signal during training. Using extensive experiments, we show that the proposed regularization leads to equivalent or better results than other VT proposals which include a local bias by changing the basic Transformer architecture, and it can drastically boost the VT final accuracy when using small-medium training sets. The code is available at https://github.com/helia95/SAR.

SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain

Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.

Design of a power processing unit with integrated telemetry for a vacuum arc thruster as part of the SeRANIS mission

In this work the design and development of a power processing unit for a vacuum arc thruster is presented. The thruster is part of the Seamless Radio Access Networks for Internet of Space (SeRANIS) mission of the University of the Bundeswehr Munich, which will work as first multifunctional laboratory in orbit with public access. In addition to the basic functionality of generating a voltage peak for igniting the thruster, the power processing unit is equipped with techniques for controlling the ignition sequence and monitoring desired key values. The ignition procedure starts with generating the first trigger signal up to the point where a full-blown plasma is established. The PPU guarantees reliable performance by blocking every additional incoming signal while the ignition sequence is under way and the separation of the satellite’s power bus before the thruster discharges. The status of the power processing unit is constantly controlled and information is provided whether ignition was successful or not. The functionality of this circuit is based on simulation before assembly and testing. In addition, the presented system was designed to pass a test cycle of mechanical, thermal and electrical tests before being declared ready for the space mission.

Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling

Plasticity of dorsal root ganglion (DRG) nociceptors in the peripheral nervous system requires new protein synthesis. This plasticity is believed to be responsible for the physiological changes seen in DRG nociceptors in animal models of chronic pain. Experiments in human DRG (hDRG) neurons also support this hypothesis, but a direct observation of nascent protein synthesis in response to a pain promoting substance, like interleukin-6 (IL-6), has not been measured in these neurons. To fill this gap in knowledge, we used acutely prepared human DRG explants from organ donors. These explants provide a physiologically relevant microenvironment, closer to in vivo conditions, allowing for the examination of functional alterations in DRG neurons reflective of human neuropathophysiology. Using this newly developed assay, we demonstrate upregulation of the target of the MNK1/2 kinases, phosphorylated eIF4E (p-eIF4E), and nascently synthesized proteins in a substantial subset of hDRG neurons following exposure to IL-6. To pinpoint the specific molecular mechanisms driving this IL-6-driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508. Treatment with eFT508 resulted in the inhibition of IL-6-induced increases in p-eIF4E and nascent proteins. Additionally, using TRPV1 as a marker for nociceptors, we found that these effects occurred in a large number of human nociceptors. Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors primarily via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain.