Characterizing Biphoton Spatial Wave Function Dynamics with Quantum Wavefront Sensing.

With an extremely high dimensionality, the spatial degree of freedom of entangled photons is a key tool for quantum foundation and applied quantum techniques. To fully utilize the feature, the essential task is to experimentally characterize the multiphoton spatial wave function including the entangled amplitude and phase information at different evolutionary stages. However, there is no effective method to measure it. Quantum state tomography is costly, and quantum holography requires additional references. Here, we introduce quantum Shack-Hartmann wavefront sensing to perform efficient and reference-free measurement of the biphoton spatial wave function. The joint probability distribution of photon pairs at the back focal plane of a microlens array is measured and used for amplitude extraction and phase reconstruction. In the experiment, we observe that the biphoton amplitude correlation becomes weak while phase correlation shows up during free-space propagation. Our work is a crucial step in quantum physical and adaptive optics and paves the way for characterizing quantum optical fields with high-order correlations or topological patterns.

Overcoming noise in quantum teleportation with multipartite hybrid entanglement.

Quantum entanglement and decoherence are the two counterforces of many quantum technologies and protocols. For example, while quantum teleportation is fueled by a pair of maximally entangled resource qubits, it is vulnerable to decoherence. Here, we propose an efficient quantum teleportation protocol in the presence of pure decoherence and without entangled resource qubits entering the Bell-state measurement. Instead, we use multipartite hybrid entanglement between the auxiliary qubits and their local environments within the open-quantum system context. With a hybrid-entangled initial state, it is the decoherence that allows us to achieve high fidelities. We demonstrate our protocol in an all-optical experiment.

Inverted loading strategy regulates the Mn-OV-Ce sites for efficient fenton-like catalysis.

Regulating interfacial active sites to improve peroxymonosulfate (PMS) activation efficiency is a hot topic in the heterogeneous catalysis field. In this study, we develop an inverted loading strategy to engineer asymmetric Mn-OV-Ce sites for PMS activation. Mn3O4@CeO2 prepared by loading CeO2 nanoparticles onto Mn3O4 nanorods exhibits the highest catalytic activity and stability, which is due to the formation of more oxygen vacancies (OV) at the Mn-OV-Ce sites, and the surface CeO2 layer effectively inhibits corrosion by preventing the loss of manganese ion active species into the solution. In situ characterizations and density functional theory (DFT) studies have revealed effective bimetallic redox cycles at asymmetric Mn-OV-Ce active sites, which promote surface charge transfer, enhance the adsorption reaction activity of active species toward pollutants, and favor PMS activation to generate (•OH, SO4•-, O2•- and 1O2) active species. This study provides a brand-new perspective for engineering the interfacial behavior of PMS activation.

Spatial confinement of styryl pyridine salt derivative in MCM-22 molecular sieve network for boosted fluorescence emission and stable ratiometric sensing of bacillus anthracis biomarkers.

In this work, a stable ratiometric nanofluorescent probe for the detection of 2,6-dipicolinic acid (DPA), a Bacillus anthracis biomarker, was developed based on confinement-induced emission enhancement of cationic styrylpyridine salt derivative L in MCM-22 molecular sieve pores. The cationic L and the lanthanide Tb3+ were loaded into the pores of the molecular sieve by electrostatic interaction with the negatively charged AlO4 tetrahedron unit, and L exhibited enhanced red fluorescence emission as a stable fluorescence reference mark in the nanoprobe platform due to the restricted molecular torsion of L in the pores of MCM-22. At the same time, the characteristic green fluorescence emission of Tb3+ can be excited by energy transfer due to the "antenna effect" of DPA. The prepared Tb-L@MCM-22 nanoprobe showed specific selectivity and stable fluorescence ratiometric detection of DPA in tap water, lake water, bovine serum and actual bacterial spores. Benefiting from the confinement-induced fluorescence enhancement effect of L in the MCM-22 molecular sieve pores, the obtained Tb-L@MCM-22 can provide a stable reference signal for the fluorescence ratiometric detection of DPA with a limit of detection (LOD) of 78.6 nM and 1.310 × 104 spores per mL. More importantly, combining of the Tb-L@MCM-22 based DPA detection test strips with a smartphone app demonstrated a stable, convenient and rapid method for detecting of anthrax biomarkers.

Sequential-Crosslinking Fibrin Glue for Rapid and Reinforced Hemostasis.

Achieving hemostasis effectively is essential for surgical success and excellent patient outcomes. However, it is challenging to develop hemostatic adhesives that are fast-acting, strongly adherent, long-lasting, and biocompatible for treating hemorrhage. In this study, a sequential crosslinking fibrin glue (SCFG) is developed, of which the first network of the fibrin glue forms in situ within 2 s to act as an initial physical barrier and locks the gelatin methacryloyl precursor for tight construction of the second network to enhance wet adhesion and durability for tissues covered with blood. The sequential crosslinking glue can provide large pressures (≈280 mmHg of burst pressure), makes strong (38 kPa of shear strength) and tough (≈60 J m-2 of interfacial toughness) interfaces with wet tissues, and outperforms commercial hemostatic agents and gelatin methacryloyl. SCFG are demonstrated as an effective and safe sealant to enhance the treatment outcomes of bleeding tissues in rat, rabbit, and pig models. The ultrafast gelation, strong adhesion and durability, excellent compatibility, and easy manufacture of SCFG make it a promising hemostatic adhesive for clinical applications.

Correction: Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

[This corrects the article DOI: 10.1371/journal.pbio.3001134.].

Is transoral endoscopic thyroidectomy safe for total thyroidectomy compared to open thyroidectomy? A propensity-score matched cohort study with papillary thyroid carcinoma.

BACKGROUND: Transoral endoscopic thyroidectomy via vestibular approach (TOETVA) has become increasingly popular in the treatment of papillary thyroid cancer (PTC). This study aimed to describe the safety and feasibility of total thyroidectomy between the TOETVA and open thyroidectomy (OT) approaches for the treatment of patients with PTC. METHODS: We retrospectively reviewed 780 consecutive patients suffering from PTC that had undergone total thyroidectomy using TOETVA (n = 107) and OT (n = 673) between April 2016 and December 2021 at our institute. Afterward, a total of 101 matched patients' surgical outcomes were compared using propensity score matching (PSM) analysis. RESULTS: Before PSM, the patients in the TOETVA group were younger (p < 0.001), had a lower body mass index (p < 0.001) and a greater female population (p < 0.001). After PSM, the TOETVA group was associated with significantly longer operative time (p < 0.001), greater blood loss (p < 0.001), total drainage amount (p < 0.001), higher C-reaction protein level (p < 0.001), better cosmetic satisfaction (p < 0.001) and quality of life (p < 0.001) and lower scar self-consciousness (p < 0.001). There was no statistical difference between the groups in the rate of parathyroid autotransplantation and bilateral lymph node dissection, the positivity of lymph node metastasis, number of dissected lymph nodes and positive lymph nodes, multifocality, postoperative level of blood calcium and parathyroid hormone (PTH), rate of PTH < 15 ng/mL, visual analog scale score, duration of hospital stay, complications, mean thyroid stimulating hormone (TSH)-stimulated Tg level before radioactive iodine, mean Tg level without TSH stimulation, and the proportion of serum Tg level of <1. CONCLUSION: TOETVA is a safe and feasible technique for better cosmetic effects and similar surgical outcomes compared to conventional open surgery for the studied patients that required total thyroidectomy.

Comparison of the endoscopic thyroidectomy via areola approach and open thyroidectomy: A propensity score matched cohort study of 302 patients in the treatment of papillary thyroid non-microcarcinoma.

Background: The endoscopic thyroidectomy via areola approach (ETAA) is widely used in patients with benign thyroid tumors and papillary thyroid microcarcinoma (PTMC). Its safety and complication rates are reported to be similar to open thyroidectomy (OT). This study aimed to evaluate the safety and feasibility of ETAA, compared with OT, in patients with papillary thyroid non-microcarcinoma (PTNMC). Methods: We retrospectively reviewed all patients with PTNMC who underwent ETAA or OT in our hospital from January 2017 to December 2021. A total of 302 patients were matched at a ratio of 1:1 by the propensity score matching (PSM) analysis and surgical outcomes. Safety and feasibility were analyzed between two groups. Results: Before PSM, patients in the ETAA group were younger (p < 0.001) and had a larger proportion of female patients (p < 0.001) with a lower BMI (p < 0.001) compared with the OT group. The ETAA group also had a higher proportion of unilateral thyroidectomy (p = 0.002). PSM was used to create a highly comparable control group. After PSM, the ETAA group had a longer operative time (p < 0.001), larger blood loss (p = 0.046) and total drainage amount (p = 0.035), with higher C-reactive protein (p = 0.023) and better cosmetic outcomes (p < 0.001). There were no significant differences in the following clinicopathologic characteristics: number of dissected positive lymph nodes, rate of recurrent laryngeal nerve signal weakened, parathyroid autotransplantation, postoperative pain, hospital stay, complications, and oncologic completeness. There was no patient converted to OT in the ETAA group and two patients suffered from persistence/recurrence in the follow-up. Conclusion: ETAA is a safe and feasible surgical approach for patients with PTNMC.

Diagnosis of cervical lymph node metastasis with thyroid carcinoma by deep learning application to CT images.

Introduction: The incidence of thyroid diseases has increased in recent years, and cervical lymph node metastasis (LNM) is considered an important risk factor for locoregional recurrence. This study aims to develop a deep learning-based computer-aided diagnosis (CAD) method to diagnose cervical LNM with thyroid carcinoma on computed tomography (CT) images. Methods: A new deep learning framework guided by the analysis of CT data for automated detection and classification of LNs on CT images is proposed. The presented CAD system consists of two stages. First, an improved region-based detection network is designed to learn pyramidal features for detecting small nodes at different feature scales. The region proposals are constrained by the prior knowledge of the size and shape distributions of real nodes. Then, a residual network with an attention module is proposed to perform the classification of LNs. The attention module helps to classify LNs in the fine-grained domain, improving the whole classification network performance. Results: A total of 574 axial CT images (including 676 lymph nodes: 103 benign and 573 malignant lymph nodes) were retrieved from 196 patients who underwent CT for surgical planning. For detection, the data set was randomly subdivided into a training set (70%) and a testing set (30%), where each CT image was expanded to 20 images by rotation, mirror image, changing brightness, and Gaussian noise. The extended data set included 11,480 CT images. The proposed detection method outperformed three other detection architectures (average precision of 80.3%). For classification, ROI of lymph node metastasis labeled by radiologists were used to train the classification network. The 676 lymph nodes were randomly divided into 70% of the training set (73 benign and 401 malignant lymph nodes) and 30% of the test set (30 benign and 172 malignant lymph nodes). The classification method showed superior performance over other state-of-the-art methods with an accuracy of 96%, true positive and negative rates of 98.8 and 80%, respectively. It outperformed radiologists with an area under the curve of 0.894. Discussion: The extensive experiments verify the high efficiency of the proposed method. It is considered instrumental in a clinical setting to diagnose cervical LNM with thyroid carcinoma using preoperative CT images. The future research can consider adding radiologists' experience and domain knowledge into the deep-learning based CAD method to make it more clinically significant. Conclusion: The extensive experiments verify the high efficiency of the proposed method. It is considered instrumental in a clinical setting to diagnose cervical LNM with thyroid carcinoma using preoperative CT images.

A Novel D-π-A Type Fluorescent Probe for Cu2+ Based on Styryl-Pyridinium Salts Conjugating Di-(2-picolyl)amine (DPA) Units.

A novel D-π-A type fluorescent probe L(NO3) for Cu (II) sensing was designed and fully characterized. The probe consists of a styryl-pyridine cation fluorescent group and a di-(2-picolyl)amine (DPA) receptor unit, which are linked by a phenyl group to form an electron donor-π-acceptor (D-π-A) conjugate system, especially the introduction of a nitrate counter anion for significantly enhanced water solubility of the probe. Fluorescence titration studies of the probe L(NO3) showed a higher selectivity for Cu2+ than other metal ions, and the emission spectrum was strongly quenched upon binding. The competitive binding assay and the low detection limit (0.932 µM) showed that the probe L(NO3) had strong anti-interference ability and excellent Cu2+ detection performance. The binding ratio of probe L(NO3) and Cu2+ was determined from Job's plot to be 1:1, which is consistent with the results obtained from X-ray crystal structures. Meanwhile, the probe showed instantaneous chemical reversibility when titrated with EDTA solution, indicating potential recycling properties of the probe. In addition, the design of inexpensive fluorescent test strips can perform the on-site and real-time detection Cu2+ with a color recognition application.

Sulfonium-Driven Neoantigen-Released DNA Nanodevice as a Precise Vaccine for Tumor Immunotherapy and Prevention.

Peptide-based neoantigen vaccines hold tremendous potential for personalized tumor immunotherapy. However, effective delivery and controllable release of antigen peptides remain major challenges in stimulating robust and sustained immune responses. Programmable DNA nanodevices provide accurate fixed positions for antigens, which are convenient for the calculation of clinical dosage, and hold great potential as precise carriers. Here, a peptide-nucleic acid conjugate was prepared, which was driven by a propargyl sulfonium-based efficient and reversible bio-orthogonal reaction under weakly alkaline conditions, and folded into regular DNA nanodevice vaccines. The well-defined nanoplatform not only exhibits outstanding stability in serum, satisfactory safety, and effective internalization by antigen-presenting cells (RAW264.7 and BMDCs) but also obviously enhances cytokine (TNF-α, IL-6, and IL-12) secretion for further immune response. In vivo, the nanovaccine cooperating with OVA model antigens and CpG adjuvants stimulated an antigen-specific CD8+T cell response, significantly preventing the lung metastases of melanoma. In the B16-OVA tumor-bearing model, the growth inhibition rate of melanoma reached up to 50%. Similarly, the DNA nanodevice with neoantigen induced up to a maximum degree of complete MC-38 tumor regression in 80% of mice, possibly owing to antigen peptide reversible release driven by sulfonium and further cross-presentation. In brief, this study demonstrates that DNA nanodevices with sulfonium centers can provide a precise, biocompatible, and effective co-delivery vaccine platform for tumor immunotherapy and prevention.

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center.

In recent years, cyclic peptides have attracted increasing attention in the field of drug discovery due to their excellent biological activities, and, as a consequence, they are now used clinically. It is, therefore, critical to seek effective strategies for synthesizing cyclic peptides to promote their application in the field of drug discovery. This paper reports a detailed protocol for the efficient synthesis of cyclic peptides using on-resin or intramolecular (intermolecular) bisalkylation. Using this protocol, linear peptides were synthesized by taking advantage of solid-phase peptide synthesis with cysteine (Cys) and methionine (Met) coupled simultaneously on the resin. Further, cyclic peptides were synthesized via bisalkylation between Met and Cys using a tunable tether and an on-tether sulfonium center. The whole synthetic route can be divided into three major processes: the deprotection of Cys on the resin, the coupling of the linker, and the cyclization between Cys and Met in a trifluoroacetic acid (TFA) cleavage solution. Furthermore, inspired by the reactivity of the sulfonium center, a propargyl group was attached to the Met to trigger thiol-yne addition and form a cyclic peptide. After that, the crude peptides were dried and dissolved in acetonitrile, separated, and then purified by high-performance liquid chromatography (HPLC). The molecular weight of the cyclic peptide was confirmed by liquid chromatography-mass spectrometry (LC-MS), and the stability of the cyclic peptide combination with the reductant was further confirmed using HPLC. In addition, the chemical shift in the cyclic peptide was analyzed by 1H nuclear magnetic resonance (1H NMR) spectra. Overall, this protocol aimed to establish an effective strategy for synthesizing cyclic peptides.

Ion exchange fabrication of lanthanide functionalized layered double hydroxides microcapsules for rapid and visual detection of anthrax biomarker.

Lanthanide ion probes have recently been considered as promising sensing materials due to their high sensitivity and good optical properties. Herein, the 3D hierarchical lanthanide functionalized layered double hydroxides microcapsules were synthesized via a facile ion exchange strategy and further developed as novel fluorescent probes for detecting trace amounts of the anthrax biomarker dipicolinicacid (DPA). Benefiting from the 3D porous superstructure and abundant unsaturated coordination sites of lanthanide ion, the ternary Ni-Fe-Ln-LDHs (Ln = Tb/Eu) not only possess a large reactive contact area to improve the sensitivity of DPA detection, but also demonstrate very fast reaction rate. The design of inexpensive fluorescent test strips can perform the on-site and real-time detection via a smartphone with a color recognition application. More prominently, the sensitivity of the system was evaluated by actual spore samples with the detection limit as low as 3.54 × 104 spores/mL. The 3D lanthanide functionalized LDHs nanoprobe constructed by ion exchange exhibits a new vision for the development of a sensing platform in other research areas.

Effects of Intraoperative Neural Tunnel in Protecting Recurrent Laryngeal Nerve: Experiences in Open, Trans Breast, and Transoral Endoscopic Thyroidectomy.

Background: Energy-based devices (EBDs) increase the risks of thermal nerve injuries. This study aimed to introduce a surgical strategy of intraoperative neural tunnel protecting (INTP) for evaluating the effect in reducing the incidence of recurrent laryngeal nerve (RLN) damage in open, trans breast, and transoral endoscopic thyroidectomy. Methods: INTP strategy was introduced: a tunnel was established and protected by endoscopic gauze along the direction of the nerve. A total of 165, 94, and 200 patients with papillary thyroid carcinoma (PTC) were to use INTP in respectively open, trans breast, and transoral endoscopic thyroidectomy as the INTP group. Additionally, 150, 95, and 225 patients who received the same methods without INTP were enrolled in the control group. Ipsilateral thyroidectomy or total thyroidectomy, and central compartment dissection were performed on the enrolled patients. Results: Clinicopathologic characteristics, surgical outcomes, and surgical complications were similar between the INTP group and the control group in open, trans breast, and transoral endoscopic thyroidectomy. The incidences of electromyography (EMG) changes in the INTP group were lower as compared to the control group in trans breast endoscopic thyroidectomy (p < 0.05). The incidence of postoperative hoarse in the INTP group was lower as compared to the control group in open and transoral endoscopic thyroidectomy (p < 0.05). Postoperative calcium levels (p < 0.01) were significantly higher, and the white blood cells (p < 0.05) and C-reactive protein levels (p < 0.01) were significantly decreased in the INTP group compared with the control group in transoral endoscopic thyroidectomy. Conclusions: This was the first instance of the INTP strategy being introduced and was found to be an effective method for protecting the RLN in open, trans breast, and transoral endoscopic thyroidectomy. Additionally, INTP helped protect other important tissues such as the parathyroid glands in transoral endoscopic thyroidectomy as well as in reducing postoperative inflammatory responses.

Micropatterned Poly(D,L-Lactide-Co-Caprolactone) Conduits With KHI-Peptide and NGF Promote Peripheral Nerve Repair After Severe Traction Injury.

Severe traction injuries after stretch to peripheral nerves are common and challenging to repair. The nerve guidance conduits (NGCs) are promising in the regeneration and functional recovery after nerve injuries. To enhance the repair of severe nerve traction injuries, in this study KHIFSDDSSE (KHI) peptides were grafted on a porous and micropatterned poly(D,L-lactide-co-caprolactone) (PLCL) film (MPLCL), which was further loaded with a nerve growth factor (NGF). The adhesion number of Schwann cells (SCs), ratio of length/width (L/W), and percentage of elongated SCs were significantly higher in the MPLCL-peptide group and MPLCL-peptide-NGF group compared with those in the PLCL group in vitro. The electromyography (EMG) and morphological changes of the nerve after severe traction injury were improved significantly in the MPLCL-peptide group and MPLCL-peptide-NGF group compared with those in the PLCL group in vivo. Hence, the NGCs featured with both bioactive factors (KHI peptides and NGF) and physical topography (parallelly linear micropatterns) have synergistic effect on nerve reinnervation after severe traction injuries.

Highly Controllable Hierarchically Porous Ag/Ag2 S Heterostructure by Cation Exchange for Efficient Hydrogen Evolution.

Establishing the hierarchical porous architectures has been considered to be the most efficient approach to realize the efficient mass diffusion and large exposed active sites of designed micro/nanomaterial catalysts for hydrogen evolution reactions (HER). In this work, the nonequivalent cation exchange strategy is developed to fabricate the hierarchically porous Ag/Ag2 S heterostructure based on the rapid cation exchange by the metal-organic framework (MOF)-derived CoS. The as-prepared Ag/Ag2 S inherits the original 3D hollow morphology of CoS with porous nature, possessing abundant S-vacancies and lattice strain simultaneously due to the coordination loss and in-situ epitaxial growth of metallic Ag on the surface. Owing to the optimizations of lattice and electronic structures, the unique hierarchically porous Ag/Ag2 S heterostructure exhibits superior catalytic performance than previously reported catalysts derived from MOF. Theoretical calculations have confirmed that the co-existence of Ag cluster and sulfur vacancies activates the electroactivity of the interfacial defective region to boost the HER process. The binding strength of the proton and energetic trend of HER has been optimized with the formation of Ag/Ag2 S heterostructure, which guarantees the efficient generation of H2 . This study opens a new strategy for the utilization of the nonequivalent cation exchange strategy to efficiently synthesize advanced electrocatalysts with high performances.

Comparison of the transoral endoscopic thyroidectomy vestibular approach and open thyroidectomy: A propensity score-matched analysis of surgical outcomes and safety in the treatment of papillary thyroid carcinoma.

BACKGROUND: The transoral endoscopic thyroidectomy vestibular approach has been demonstrated to have similar surgical outcomes as open thyroidectomy for selected papillary thyroid carcinomas. This study aimed to evaluate and compare the surgical outcomes and safety of the transoral endoscopic thyroidectomy vestibular approach with those of open thyroidectomy in the treatment of papillary thyroid carcinoma with a diameter between >1 cm and ≤3.5cm. METHODS: We retrospectively reviewed all patients who had papillary thyroid carcinoma that was between >1 cm and ≤3.5 cm in diameter and who had undergone the transoral endoscopic thyroidectomy vestibular approach (n = 96) or an open thyroidectomy (n = 425) from January 2017 to June 2020. We then performed 1:1 propensity score matching, yielding 78 matched pairs. Afterward, surgical outcomes and follow-up data were compared between the 2 matched groups. RESULTS: Compared with the matched open thyroidectomy group, the papillary thyroid carcinoma group had a significantly longer operative time (P < .001), more blood loss (P < .05), higher postoperative white blood cell count (P < .05), higher C-reactive protein (P < .001), more total drainage volume (P < .001), increased surgical cost (P < .05), better cosmetic satisfaction (P <.001), lower scar self-consciousness (P < .001), and better quality of life (P < .001). We observed no significant differences in the incidence of other outcomes, including the number of retrieved lymph nodes and metastatic central lymph nodes, the rate of intraoperative recurrent laryngeal nerve signal weakened and parathyroid autotransplantation, visual analog scale scores for pain, drainage duration, postoperative hospital stay, rate of complications, and oncologic completeness. We observed no conversion to open thyroidectomy and no intraoperative capsular disruption in the transoral endoscopic thyroidectomy vestibular approach group. There was 1 case of persistent nodal disease in the transoral endoscopic thyroidectomy vestibular approach group. No recurrence was observed in the 2 groups during the follow-up period. CONCLUSION: The transoral endoscopic thyroidectomy vestibular approach is feasible in selected patients with papillary thyroid carcinoma, not only because it is cosmetically advantageous but also because it is surgical and oncologically safe and may be an optional surgical method for treating papillary thyroid carcinomas having a diameter between >1 cm and ≤3.5 cm.

Robust coherent control of solid-state spin qubits using anti-Stokes excitation.

Optically addressable solid-state color center spin qubits have become important platforms for quantum information processing, quantum networks and quantum sensing. The readout of color center spin states with optically detected magnetic resonance (ODMR) technology is traditionally based on Stokes excitation, where the energy of the exciting laser is higher than that of the emission photons. Here, we investigate an unconventional approach using anti-Stokes excitation to detect the ODMR signal of silicon vacancy defect spin in silicon carbide, where the exciting laser has lower energy than the emitted photons. Laser power, microwave power and temperature dependence of the anti-Stokes excited ODMR are systematically studied, in which the behavior of ODMR contrast and linewidth is shown to be similar to that of Stokes excitation. However, the ODMR contrast is several times that of the Stokes excitation. Coherent control of silicon vacancy spin under anti-Stokes excitation is then realized at room temperature. The spin coherence properties are the same as those of Stokes excitation, but with a signal contrast that is around three times greater. To illustrate the enhanced spin readout contrast under anti-Stokes excitation, we also provide a theoretical model. The experiments demonstrate that the current anti-Stokes excitation ODMR approach has promising applications in quantum information processing and quantum sensing.

Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Here, we discover that farnesyl pyrophosphate (FPP), a metabolic intermediate of the MVA pathway, functions as a newly identified danger signal to trigger acute cell death leading to neuron loss in stroke. Harboring both a hydrophobic 15-carbon isoprenyl chain and a heavily charged pyrophosphate head, FPP leads to acute cell death independent of its downstream metabolic pathways. Mechanistically, extracellular calcium influx and the cation channel transient receptor potential melastatin 2 (TRPM2) exhibit essential roles in FPP-induced cell death. FPP activates TRPM2 opening for ion influx. Furthermore, in terms of a mouse model constructing by middle cerebral artery occlusion (MCAO), FPP accumulates in the brain, which indicates the function of the FPP and TRPM2 danger signal axis in ischemic injury. Overall, our data have revealed a novel function of the MVA pathway intermediate metabolite FPP as a danger signal via transient receptor potential cation channels.