CRF regulates pain sensation by enhancement of corticoaccumbal excitatory synaptic transmission.

Both peripheral and central corticotropin-releasing factor (CRF) systems have been implicated in regulating pain sensation. However, compared with the peripheral, the mechanisms underlying central CRF system in pain modulation have not yet been elucidated, especially at the neural circuit level. The corticoaccumbal circuit, a structure rich in CRF receptors and CRF-positive neurons, plays an important role in behavioral responses to stressors including nociceptive stimuli. The present study was designed to investigate whether and how CRF signaling in this circuit regulated pain sensation under physiological and pathological pain conditions. Our studies employed the viral tracing and circuit-, and cell-specific electrophysiological methods to label the CRF-containing circuit from the medial prefrontal cortex to the nucleus accumbens shell (mPFCCRF-NAcS) and record its neuronal propriety. Combining optogenetic and chemogenetic manipulation, neuropharmacological methods, and behavioral tests, we were able to precisely manipulate this circuit and depict its role in regulation of pain sensation. The current study found that the CRF signaling in the NAc shell (NAcS), but not NAc core, was necessary and sufficient for the regulation of pain sensation under physiological and pathological pain conditions. This process was involved in the CRF-mediated enhancement of excitatory synaptic transmission in the NAcS. Furthermore, we demonstrated that the mPFCCRF neurons monosynaptically connected with the NAcS neurons. Chronic pain increased the protein level of CRF in NAcS, and then maintained the persistent NAcS neuronal hyperactivity through enhancement of this monosynaptic excitatory connection, and thus sustained chronic pain behavior. These findings reveal a novel cell- and circuit-based mechanistic link between chronic pain and the mPFCCRF → NAcS circuit and provide a potential new therapeutic target for chronic pain.

Engineering a hyaluronic acid-encapsulated tumor-targeted nanoplatform with sensitized chemotherapy and a photothermal effect for enhancing tumor therapy.

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O2 self-supplied nanomodules (CuS@DOX/CaO2-HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO2-HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO2) and doxorubicin (DOX), and its surface is further modified with HA. CuS@DOX/CaO2-HA underwent photothermal treatment to release DOX and CaO2. Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO2 reacts with water to produce Ca2+, H2O2 and O2, which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO2-HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO2-HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways.

Comparison of clinical characteristics and prognosis in endometrial carcinoma with different pathological types: a retrospective population-based study.

BACKGROUND: Endometrial carcinoma (EC) is the second most common gynecological malignancy, and the differences between different pathological types are not entirely clear. Here, we retrospectively collected eligible EC patients to explore their differences regarding clinical characteristics and prognosis. METHODS: Five hundred seventy EC patients from the First Affiliated Hospital of Zhengzhou University were included. Prognostic factors were measured using the univariate/multivariate Cox models. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively. RESULTS: In total, 396 patients with uterine endometrioid carcinoma (UEC), 106 patients with uterine serous carcinoma (USC), 34 patients with uterine mixed carcinoma (UMC), and 34 patients with uterine clear cell carcinoma (UCCC) were included. Comparison of baseline characteristics revealed patients diagnosed with UEC were younger, had more early clinical stage, and had lower incidence of menopause and lymph node metastasis. Compared to UEC, other pathological EC obtained more unfavorable OS (UCCC: HR = 12.944, 95%CI = 4.231-39.599, P < 0.001; USC: HR = 5.958, 95%CI = 2.404-14.765, P < 0.001; UMC: HR = 1.777, 95%CI = 0.209-15.114, P = 0.599) and PFS (UCCC: HR = 8.696, 95%CI = 1.972-38.354, P = 0.004; USC: HR = 4.131, 95%CI = 1.243-13.729, P = 0.021; UMC: HR = 5.356, 95%CI = 0.935-30.692, P = 0.060). Compared with UEC patients, the OS of UCCC patients in stage I-II and USC patients in stage III-IV were significantly worse, while UMC patients in stage I-II favored poorer PFS. The OS of UCCC patients receiving no postoperative adjuvant therapy or chemotherapy alone were significantly worse. CONCLUSIONS: The baseline characteristics of UEC and other rare EC types varied greatly, and the prognostic significance of different pathological types on EC patients depended on clinical tumor stages and therapeutic options.

CWC22-Mediated Alternative Splicing of Spp1 Regulates Nociception in Inflammatory Pain.

Increasing evidence suggests that alternative splicing plays a critical role in pain, but its underlying mechanism remains elusive. Herein, we employed complete Freund's adjuvant (CFA) to induce inflammatory pain in mice. A combination of genomics research techniques, lentivirus-based genetic manipulations, behavioral tests, and molecular biological technologies confirmed that splicing factor Cwc22 mRNA and CWC22 protein were elevated in the spinal dorsal horn at 3 days after CFA injection. Knockdown of spinal CWC22 by lentivirus transfection (lenti-shCwc22) reversed CFA-induced thermal hyperalgesia and mechanical allodynia, whereas upregulation of spinal CWC22 (lenti-Cwc22) in naïve mice precipitated pain. Comprehensive transcriptome and genome analysis identified the secreted phosphoprotein 1 (Spp1) as a potential gene of CWC22-mediated alternative splicing, however, only Spp1 splicing variant 4 (Spp1 V4) was involved in thermal and mechanical nociceptive regulation. In conclusion, our findings demonstrate that spinal CWC22 regulates Spp1 V4 to participate in CFA-induced inflammatory pain. Blocking CWC22 or CWC22-mediated alternative splicing may provide a novel therapeutic target for the treatment of persistent inflammatory pain.

The construction of hierarchical assemblies with in situ generation of chemotherapy drugs to enhance the efficacy of chemodynamic therapy for multi-modal anti-tumor treatments.

The effectiveness of chemodynamic therapy (CDT) in cancer treatment is limited by insufficient endogenous H2O2 levels in tumor tissue and an increasing ratio of high valence metal ions. To overcome these challenges, a novel nanotherapeutic approach, named GOx-CuCaP-DSF, has been proposed. This approach involves the design of nanotherapeutics that aim to self-supply H2O2 within cancer cells and provide a supplement of low valence metal ions to enhance the performance of CDT. GOx-CuCaP-DSF nanotherapeutics are engineered by incorporating glucose oxidase (GOx) into Ca2+-doped calcium phosphate (CaP) nanoparticles and loading disulfiram (DSF) through surface adsorption. Under the tumor microenvironment, GOx catalyzes the conversion of tumor-overexpressed glucose (Glu) to liberate H2O2. The degradation of CaP further lowers the pH, facilitating the release of Cu2+ ions and DSF. The rapid reaction between Cu2+ and DSF leads to the generation of Cu+, increasing the Cu+/Cu2+ ratio and promoting the Cu+-based Fenton reaction, which enhances the efficiency of CDT. Simultaneously, DSF undergoes conversion to diethyldithiocarbamate acid (ET), forming a copper(II) complex (Cu(II)ET) by strong chelation with Cu ions. This Cu(II)ET complex, a potent chemotherapeutic drug, exhibits a synergistic therapeutic effect in combination with CDT. Moreover, the elevated Cu+ species resulting from DSF reaction promotes the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Overall, the strategy of integrating the chemodynamic therapy efficiency of the Fenton reaction with the activation of efficacious cuproptosis using a chemotherapeutic drug presents a promising avenue for enhancing the effectiveness of multi-modal anti-tumor treatments.

Caveolin-1 is essential for the increased release of glutamate in the anterior cingulate cortex in neuropathic pain mice.

Neuropathic pain has a complex pathogenesis. Here, we examined the role of caveolin-1 (Cav-1) in the anterior cingulate cortex (ACC) in a chronic constriction injury (CCI) mouse model for the enhancement of presynaptic glutamate release in chronic neuropathic pain. Cav-1 was localized in glutamatergic neurons and showed higher expression in the ACC of CCI versus sham mice. Moreover, the release of glutamate from the ACC of the CCI mice was greater than that of the sham mice. Inhibition of Cav-1 by siRNAs greatly reduced the release of glutamate of ACC, while its overexpression (induced by injecting Lenti-Cav-1) reversed this process. The chemogenetics method was then used to activate or inhibit glutamatergic neurons in the ACC area. After 21 days of injection of AAV-hM3Dq in the sham mice, the release of glutamate was increased, the paw withdrawal latency was shortened, and expression of Cav-1 in the ACC was upregulated after intraperitoneal injection of 2 mg/kg clozapine N-oxide. Injection of AAV-hM4Di in the ACC of CCI mice led to the opposite effects. Furthermore, decreasing Cav-1 in the ACC in sham mice injected with rAAV-hM3DGq did not increase glutamate release. These findings suggest that Cav-1 in the ACC is essential for enhancing glutamate release in neuropathic pain.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

Corticotropin-releasing factor neurones in the paraventricular nucleus of the hypothalamus modulate isoflurane anaesthesia and its responses to acute stress in mice.

BACKGROUND: Corticotropin-releasing factor (CRF) neurones in the paraventricular nucleus (PVN) of the hypothalamus (PVNCRF neurones) can promote wakefulness and are activated under anaesthesia. However, whether these neurones contribute to anaesthetic effects is unknown. METHODS: With a combination of chemogenetic and molecular approaches, we examined the roles of PVNCRF neurones in isoflurane anaesthesia in mice and further explored the underlying cellular and molecular mechanisms. RESULTS: PVN neurones exhibited increased Fos expression during isoflurane anaesthesia (mean [standard deviation], 218 [69.3] vs 21.3 [7.3]; P<0.001), and ∼75% were PVNCRF neurones. Chemogenetic inhibition of PVNCRF neurones facilitated emergence from isoflurane anaesthesia (11.7 [1.1] vs 13.9 [1.2] min; P=0.001), whereas chemogenetic activation of these neurones delayed emergence from isoflurane anaesthesia (16.9 [1.2] vs 13.9 [1.3] min; P=0.002). Isoflurane exposure increased CRF protein expression in PVN (4.0 [0.1] vs 2.2 [0.3], respectively; P<0.001). Knockdown of CRF in PVNCRF neurones mimicked the effects of chemogenetic inhibition of PVNCRF neurones in facilitating emergence (9.6 [1.1] vs 13.0 [1.4] min; P=0.003) and also abolished the effects of chemogenetic activation of PVNCRF neurones on delaying emergence from isoflurane anaesthesia (10.3 [1.3] vs 16.0 [2.6] min; P<0.001). Acute, but not chronic, stress delayed emergence from isoflurane anaesthesia (15.5 [1.5] vs 13.0 [1.4] min; P=0.004). This effect was reversed by chemogenetic inhibition of PVNCRF neurones (11.7 [1.6] vs 14.7 [1.4] min; P=0.001) or knockdown of CRF in PVNCRF neurones (12.3 [1.5] vs 15.3 [1.6] min; P=0.002). CONCLUSIONS: CRF neurones in the PVN of the hypothalamus neurones modulate isoflurane anaesthesia and acute stress effects on anaesthesia through CRF signalling.

Retrieval-Based Factorization Machines for Human Click Behavior Prediction.

Human click behavior prediction is crucial for recommendation scenarios such as online commodity or advertisement recommendation, as it is helpful to improve the quality and user satisfaction of services. In recommender systems, the concept of click-through rate (CTR) is used to estimate the probability that a user will click on a recommended candidate. Many methods have been proposed to predict CTR and achieved good results. However, they usually optimize the parameters through a global objective function such as minimizing logloss or root mean square error (RMSE) for all training samples. Obviously, they intend to capture global knowledge of user click behavior but ignore local information. In this work, we propose a novel approach of retrieval-based factorization machines (RFM) for CTR prediction, which can effectively predict CTR by combining global knowledge which is learned from the FM method with the neighbor-based local information. We also leverage the clustering technique to partition the large training set into multiple small regions for efficient retrieval of neighbors. We evaluate our RFM model on three public datasets. The experimental results show that RFM performs better than other models in metrics of RMSE, area under ROC (AUC), and accuracy. Moreover, it is efficient because of the small number of model parameters.

Surface Modification, Topographic Design and Applications of Superhydrophobic Systems.

Superhydrophobic surfaces with expanded wetting behaviors, like tunable adhesion, hybrid surface hydrophobicity and smart hydrophobic switching have attracted increasing attention due to their broad applications. Herein, the construction methods, mechanisms and advanced applications of special superhydrophobicity are reviewed, and hydro/superhydrophobic modifications are categorized and discussed based on their surface chemistry, and topographic design. The formation and maintenance of special superhydrophobicity in the metastable state are also examined and explored. In addition, particular attention is paid to the use of special wettability in various applications, such as membrane distillation, droplet-based electricity generators and anti-fogging surfaces. Finally, the challenges for practical applications and future research directions are discussed.

Topographical Design and Thermal-Induced Organization of Interfacial Water Structure to Regulate the Wetting State of Surfaces.

Smart surfaces with superhydrophobic/superhydrophilic characteristics can be controlled by external stimuli, such as temperature. These transitions are attributed to the molecular-level conformation of the grafted polymer chains due to the varied interactions at the interface. Here, tunable surfaces were prepared by grafting two well-known thermo-responsive polymers, poly(N-isopropylacrylamide) (PNIPAM) and poly(oligoethylene glycol)methyl ether acrylate (POEGMA188) onto micro-pollen particles of uniform morphology and roughness. Direct Raman spectra and thermodynamic analyses revealed that above the lower critical solution temperature, the bonded and free water at the interface partially transformed to intermediate water that disrupted the "water cage" surrounding the hydrophobic groups. The increased amounts of intermediate water produced hydrogen bonding networks that were less ordered around the polymer grafted microparticles, inducing a weaker binding interaction at the interface and a lower tendency to wet the surface. Combining the roughness factor, the bulk surface assembled by distinct polymer-grafted-pollen microparticles (PNIPAM or POEGMA188) could undergo a different wettability transition for liquid under air, water, and oil. This work identifies new perspectives on the interfacial water structure variation at a multiple length scale, which contributed to the temperature-dependent surface wettability transition. It offers inspiration for the application of thermo-responsive surface to liquid-gated multiphase separation, water purification and harvesting, biomedical devices, and printing.

Cancer cell membrane targeting and red light-triggered carbon monoxide (CO) release for enhanced chemotherapy.

Chemotherapy assisted by carbon monoxide (CO) gas therapy is an emerging powerful cancer therapeutic modality. However, the effective delivery and controlled release of CO in tumor cells remain a challenge. Herein, a cell membrane bionic nano delivery system (RBC-H@DOX/3-HF@MSN, termed as RHM) was designed to selectively accumulate in tumors and generate CO in situ upon red light irradiation for the combination of chemotherapy and gas therapy. CO significantly improves the therapeutic effect of DOX from 29.0% to 82.4%.

Synthesis of silver nanoclusters in colloidal scaffold for biolabeling and antimicrobial applications.

A robust method to prepare silver nanoclusters (AgNCs) inside a methacrylic acid-ethyl acrylate (MAA-EA) nanogel is proposed, where AgNCs were produced within the nanogel scaffold via UV-photoreduction. The impact of UV irradiation time on the formation of AgNCs and their application in biolabeling and antimicrobial properties were examined. The AgNCs formation is described by two stages; (1) Agn (n = 2-8) nanoclusters formation between 0 and 25 min, and (2) larger silver nanoparticles (AgNPs) formed via aggregation inside the nanogel. The antimicrobial performance depended on the size and concentration of silver ions (Ag+). A maximum inhibitory concentration (MIC) of 1.1 ppm was observed for antimicrobial test with yeast, and a MIC of 11 and 22 ppm was recorded for Escherichia. coli and Staphylococcus aureus respectively. Combining with the green illumination property of AgNCs (emitted at 525 nm) with dead yeast, it could be used for biolabeling. By tuning the size through photoirradiation, the nanogel templated AgNCs is a promising candidate for antimicrobial and biolabeling applications.

Local Privacy Protection for Sensitive Areas in Multiface Images.

The privacy protection for face images aims to prevent attackers from accurately identifying target persons through face recognition. Inspired by goal-driven reasoning (reverse reasoning), this paper designs a goal-driven algorithm of local privacy protection for sensitive areas in multiface images (face areas) under the interactive framework of face recognition algorithm, regional growth, and differential privacy. The designed algorithm, named privacy protection for sensitive areas (PPSA), is realized in the following manner: Firstly, the multitask cascaded convolutional network (MTCNN) was adopted to recognize the region and landmark of each face. If the landmark overlaps a subgraph divided from the original image, the subgraph will be taken as the seed for regional growth in the face area, following the growth criterion of the fusion similarity measurement mechanism (FSMM). Different from single-face privacy protection, multiface privacy protection needs to deal with an unknown number of faces. Thus, the allocation of the privacy budget ε directly affects the operation effect of the PPSA algorithm. In our scheme, the total privacy budget ε is divided into two parts: ε_1 and ε_2. The former is evenly allocated to each seed, according to the estimated number of faces ρ contained in the image, while the latter is allocated to the other areas that may consume the privacy budget through dichotomization. Unlike the Laplacian (LAP) algorithm, the noise error of the PPSA algorithm will not change with the image size, for the privacy protection is limited to the face area. The results show that the PPSA algorithm meets the requirements ε-Differential privacy, and image classification is realized by using different image privacy protection algorithms in different human face databases. The verification results show that the accuracy of the PPSA algorithm is improved by at least 16.1%, the recall rate is improved by at least 2.3%, and F1-score is improved by at least 15.2%.

VTA-NAc glutaminergic projection involves in the regulation of pain and pain-related anxiety.

Background: Besides the established role of dopamine neurons and projections in nociceptive stimuli, the involvement of ventral tegmental area (VTA) glutamatergic projections to nucleus accumbens (NAc) in pain remains unknown. In the present study, we aimed to examine the role of VTA glutamatergic projections to NAc in painful stimuli and its related behavioral changes. Methods: Unilateral chronic constrictive injury (CCI) of sciatic nerve or intraplantar hind paw injections (i.pl.) of complete Freund's adjuvant (CFA) were used to develop pathological pain models in wild-type and VGluT2-Cre mice. The involvement of VTA glutamatergic neurons with projections to NAc in CCI-induced pain model was noted by c-Fos labeling and firing rate recordings. Pain response and pain-related behavior changes to the artificial manipulation of the VTA glutamatergic projections to NAc were observed by Hargreaves tests, von Frey tests, open field tests, elevated maze tests, and sucrose preference tests. Results: Glutamatergic neurons in VTA had efferent inputs to shell area of the NAc. The CCI pain model significantly increased neuronal activity and firing rate in VTA glutamate neurons with projections to NAc. The photoinhibition of these glutamatergic projections relieved CCI-induced neuropathic pain and CFA-induced acute and chronic inflammatory pain. Moreover, pathological neuropathic pain-induced anxiety and less sucrose preference were also relieved by inhibiting the VTA glutamatergic projections to NAc. Conclusion: Together, glutamatergic inputs from VTA to NAc contribute to chronic neuropathic and inflammatory pain and pain-related anxiety and depressive behaviors, providing a mechanism for developing novel therapeutic methods.

Sustainable Superhydrophobic Surface with Tunable Nanoscale Hydrophilicity for Water Harvesting Applications.

Superwettable surfaces show great potential in water harvesting applications, however, a scalable water harvesting surface remains elusive due to the trade-off between water deposition and transport. Herein, we report a unique superhydrophobic surface with tunable nanoscale hydrophilicity constructed by structured Pickering emulsions. Preferential exposure of the cellulose nanocrystal's outer surface and wax microspheres accelerates droplet deposition allowing for the manipulation of droplet mobility. Appropriate tuning of the wetting characteristics of the surfaces, optimizing the hydrophobicity and density of the water affinity nanodomains enhance the water deposition rate without the sacrifice of water transport rate, achieving an optimal water harvesting flux of 3.402 L m-2 h-1 for a plate and 5.02 L m-2 h-1 for a mesh. This hydrophilic/superhydrophobic surface allows the controllable manipulation of droplet nucleation and removal to enhance the water harvesting efficiency.

Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain.

Long-term limb nerve injury often leads to mirror-image pain (MIP), an abnormal pain sensation in the limb contralateral to the injury. Although it is clear that MIP is mediated in part by central nociception processing, the underlying mechanisms remain poorly understood. The anterior cingulate cortex (ACC) is a key brain region that receives relayed peripheral nociceptive information from the contralateral limb. In this study, we induced MIP in male mice, in which a unilateral chronic constrictive injury of the sciatic nerve (CCI) induced a decreased nociceptive threshold in both hind limbs and an increased number of c-Fos-expressing neurons in the ACC both contralateral and ipsilateral to the injured limb. Using viral-mediated projection mapping, we observed that a portion of ACC neurons formed monosynaptic connections with contralateral ACC neurons. Furthermore, the number of cross-callosal projection ACC neurons that exhibited c-Fos signal was increased in MIP-expressing mice, suggesting enhanced transmission between ACC neurons of the two hemispheres. Moreover, selective inhibition of the cross-callosal projection ACC neurons contralateral to the injured limb normalized the nociceptive sensation of the uninjured limb without affecting the increased nociceptive sensation of the injured limb in CCI mice. In contrast, inhibition of the non-cross-callosal projection ACC neurons contralateral to the injury normalized the nociceptive sensation of the injured limb without affecting the MIP exhibited in the uninjured limb. These results reveal a circuit mechanism, namely, the cross-callosal projection of ACC between two hemispheres, that contributes to MIP and possibly other forms of contralateral migration of pain sensation.SIGNIFICANCE STATEMENT Mirror-image pain (MIP) refers to the increased pain sensitivity of the contralateral body part in patients with chronic pain. This pathology requires central processing, yet the mechanisms are less known. Here, we demonstrate that the cross-callosal projection neurons in the anterior cingulate cortex (ACC) contralateral to the injury contribute to MIP exhibited in the uninjured limb, but do not affect nociceptive sensation of the injured limb. In contrast, the non-cross-callosal projection neurons in the ACC contralateral to the injury contribute to nociceptive sensation of the injured limb, but do not affect MIP exhibited in the uninjured limb. Our study depicts a novel cross-callosal projection of ACC that contributes to MIP, providing a central mechanism for MIP in chronic pain state.

Behaviors Related to Psychiatric Disorders and Pain Perception in C57BL/6J Mice During Different Phases of Estrous Cycle.

Robust sex difference among humans regarding psychiatry- and pain-related behaviors is being researched; however, the use of female mice in preclinical research is relatively rare due to an unchecked potential behavioral variation over the estrous cycle. In the present study, a battery of psychiatry- and pain-related behaviors are examined under physiological condition in female C57BL/6J mice over different estrous cycle phases: proestrus, estrous, metestrous, diestrous. Our behavioral results reveal that there is no significant difference over different phases of the estrous cycle in social interaction test, sucrose preference test, tail suspension test, open field test, marble burying test, novelty-suppressed feeding test, Hargreaves thermal pain test, and Von Frey mechanical pain test. These findings implicate those psychiatry- and pain-related behaviors in normal female C57BL/6J mice appear to be relatively consistent throughout the estrous cycle; the estrous cycle might not be a main contributor to female C57BL/6J mice's variability of behaviors.

Coherent narrow-linewidth optical frequency synthesis across the optical telecommunication band.

Broadband, coherent narrow-linewidth optical frequency synthesis is of crucial importance in dual-comb interferometric measurement. Here we present a detailed description of the construction and performance characterization of a hertz-level linewidth coherent optical frequency synthesizer across the optical telecommunication band. A narrow-linewidth cavity-stabilized laser at 1565.00 nm is built and coherently transferred through a fiber link with an additional fractional frequency instability of 2.0×10-16 at 1 s averaging time. Broadband, coherent optical frequency synthesis is then achieved by steering one mode of a laser frequency comb with the transferred optical frequency oscillation. By beating with a 1542.14 nm ultra-stable cavity-stabilized laser, the evaluated fractional frequency stability and absolute linewidth of the nearest synthesized optical oscillation are 3.5×10-15 at 1 s averaging time and 1.8 Hz, respectively. According to the ultra-low-noise feature of the utilized laser frequency comb of 4.7×10-17 at 1 s averaging time, the synthesized optical frequency oscillations could maintain the high coherence across the comb's output bandwidth.

MKP1 in the medial prefrontal cortex modulates chronic neuropathic pain via regulation of p38 and JNK1/2.

Aim: The medial prefrontal context (mPFC) plays pivotal roles in initiation, development, and maintenance of chronic pain, whereas the underlying molecular mechanisms remain elusive, which invited investigation of potential involvement of MKP1 in mPFC in mice in neuropathic pain, and its cellular and molecular mechanisms.Materials and methods: Neuropathic pain model was established in adult male Kunming mice via chronic constrictive injury (CCI) of the sciatic nerve. Paw withdrawal latency (PWL) was measured at the plantar area by radiant heat test. Stereotaxic microinjection was applied in mice as per the atlas of Mouse Brain in Stereotaxic Coordinates. mRNA levels of MKP1 in mPFC in CCI mice were assessed by RT-PCR; protein expressions of MKP1, p-p38, p-JNK and p-ERK in mPFC in CCI mice were analyzed by Western blotting, and expressions of the c-Fos in mPFC in CCI mice evaluated by immunohistochemistry. Moreover, Lenti-MKP1 particles or BCI treatment was employed to inhibit MKP1 in mPFC contralateral to the injury.Results: MKP1 was activated and persistently upregulated in mPFC neurons in CCI mice. Inhibition of MKP1 in the mPFC contralateral to the injury could reverse CCI-induced pain behavior and neuronal activity either via employment of Lenti-MKP1 particles or BCI treatment. MKP1 in the mPFC modulated neuropathic pain via dephosphorization of p38 and JNK1/2.Conclusion: The findings demonstrated that MKP1 in mPFC could play a paramount role in the modulation of neuropathic pain, which might be associated to the increased neuronal excitability in the mPFC and downregulated p-p38 and p-JNK expression.