TET1-Lipid Nanoparticle Encapsulating Morphine for Specific Targeting of Peripheral Nerve for Pain Alleviation.

Background: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia. Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA. Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001). Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.

Engineering Internal and External Low-Coordination Atoms in Nickel-Organic Framework Nanoarrays to Promote the Electrochemical Oxygen Evolution Reaction.

Monometallic nickel-organic frameworks based on a carboxylated ligand [2,6-naphthalenedicarboxylic acid (Ni-NDC)] have abundant and uniformly distributed single-atom Ni sites, enabling superior oxygen evolution reaction (OER) activity. In theory, most of the Ni atoms inside Ni-NDC microcrystals are coordinatively saturated except for the surface. Therefore, there are no accessible low-coordination atoms (LCAs) as electrocatalytic sites for the OER. One effective way is to expose more LCAs by preparing self-supporting Ni-NDC nanoarrays (Ni-NDC NAs) with hierarchical secondary structural units. Another effective method is to create more internal LCAs by removing partial ligands or coordination atoms attached to the Ni atoms. Herein, by combining the two strategies, we engineered LCAs in the interior and exterior of Ni-NDC to synergistically accelerate the OER. In brief, ultrathick "brick-like" Ni-NDC NAs were first prepared with dissolution and coordination effects of NDC on self-sacrificial templates of "agaric-like" nickel hydroxide nanoarrays [Ni(OH)2 NAs]. Subsequently, dual-coordinated NDC was partially replaced by monocoordinated 2-naphthoic acid (NA). The Ni-NDC NAs were further tailed into ultrathin "liner leaf-like" nanoneedle arrays (LCAs-Ni-NDC NAs). As a consequence, the LCAs-Ni-NDC NAs have more internal and external LCAs, which can deliver an OER performance that is superior to that of Ni-NDC NAs.

Codelivery of Dual Gases with Metal-Organic Supramolecular Cage-Based Microenvironment-Responsive Nanomedicine for Atherosclerosis Therapy.

Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.

Development and validation of a novel nomogram model for identifying risk of prolonged length of stay among patients receiving free vascularized flap reconstruction of head and neck cancer.

Background: The aim of the present study was to build and internally validate a nomogram model for predicting prolonged length of stay (PLOS) among patients receiving free vascularized flap reconstruction of head and neck cancer (HNC). Methods: A retrospective clinical study was performed at a single center, examining patients receiving free vascularized flap reconstruction of HNC from January 2011 to January 2019. The variables were obtained from the electronic information system. The primary outcome measure was PLOS. Univariate and multivariate analyses were used to find risk factors for predicting PLOS. A model was then built according to multivariate results. Internal validation was implemented via 1000 bootstrap samples. Results: The study included 1047 patients, and the median length of stay (LOS) was 13.00 (11.00, 16.00) days. Multivariate analysis showed that flap types ((radial forearm free flap (odds ratio [OR] = 2.238; 95% CI, 1.403-3.569; P = 0.001), free fibula flap (OR = 3.319; 95% CI, 2.019-4.882; P < 0.001)), duration of surgery (OR = 1.002; 95% CI, 1.001-1.003; P = 0.004), postoperative complications (OR = 0.205; 95% CI, 0.129-0.325; P = P < 0.001) and unplanned reoperation (OR = 0.303; 95% CI, 0.140-0.653; P = 0.002) were associated with PLOS. In addition to these variables, blood transfusion was comprised in the model. The AUC of the model was 0.78 (95% CI, 0.711-0.849) and 0.725 (95% CI, 0.605-0.845) in the primary and internal validation cohorts, respectively. The DCA revealed the clinical utility of the current model when making intervention decisions within the PLOS possibility threshold range of 0.2-0.8. Conclusions: Our study developed a nomogram that exhibits a commendable level of accuracy, thereby aiding clinicians in assessing the risk of PLOS among patients receiving free vascularized flap reconstruction for HNC.

Predicting the geographical distribution and niche characteristics of Cotoneaster multiflorus based on future climate change.

Introduction: Arid and semi-arid regions are climate-sensitive areas, which account for about 40% of the world's land surface area. Future environment change will impact the environment of these area, resulting in a sharp expansion of arid and semi-arid regions. Cotoneaster multiflorus is a multi-functional tree species with extreme cold, drought and barren resistance, as well as ornamental and medicinal functions. It was found to be one of the most important tree species for ecological restoration in arid and semi-arid areas. However, bioclimatic factors play an important role in the growth, development and distribution of plants. Therefore, exploring the response pattern and ecological adaptability of C. multiflorus to future climate change is important for the long-term ecological restoration of C. multiflorus in arid and semi-arid areas. Methods: In this study, we predicted the potential distribution of C. multiflorus in China under different climate scenarios based on the MaxEnt 2.0 model, and discussed its adaptability and the major factors affecting its geographical distribution. Results: The major factors that explained the geographical distribution of C. multiflorus were Annual precipitation (Bio12), Min air temperature of the coldest month (Bio6), and Mean air temperature of the coldest quarter (Bio11). However, C. multiflorus could thrive in environments where Annual precipitation (Bio12) >150 mm, Min air temperature of the coldest month (Bio6) > -42.5°C, and Mean air temperature of the coldest quarter (Bio11) > -20°C, showcasing its characteristics of cold and drought tolerance. Under different future climate scenarios, the total suitable area for C. multiflorus ranged from 411.199×104 km² to 470.191×104 km², which was 0.8~6.14 percentage points higher than the current total suitable area. Additionally, it would further shift towards higher latitude. Discussion: The MaxEnt 2.0 model predicted the potential distribution pattern of C. multiflorus in the context of future climate change, and identified its ecological adaptability and the main climatic factors affecting its distribution. This study provides an important theoretical basis for natural vegetation restoration in arid and semi-arid areas.

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Self-Powered Biomimetic Pressure Sensor Based on Mn-Ag Electrochemical Reaction for Monitoring Rehabilitation Training of Athletes.

Self-powered pressure detection using smart wearable devices is the subject of intense research attention, which is intended to address the critical need for prolonged and uninterrupted operations. Current piezoelectric and triboelectric sensors well respond to dynamic stimuli while overlooking static stimuli. This study proposes a dual-response potentiometric pressure sensor that responds to both dynamic and static stimuli. The proposed sensor utilizes interdigital electrodes with MnO2/carbon/polyvinyl alcohol (PVA) as the cathode and conductive silver paste as the anode. The electrolyte layer incorporates a mixed hydrogel of PVA and phosphoric acid. The optimized interdigital electrodes and sandpaper-like microstructured surface of the hydrogel electrolyte contribute to enhanced performance by facilitating an increased contact area between the electrolyte and electrodes. The sensor features an open-circuit voltage of 0.927 V, a short-circuit current of 6 µA, a higher sensitivity of 14 mV/kPa, and outstanding cycling performance (>5000 cycles). It can accurately recognize letter writing and enable capacitor charging and LED lighting. Additionally, a data acquisition and display system employing the proposed sensor, which facilitates the monitoring of athletes' rehabilitation training, and machine learning algorithms that effectively guide rehabilitation actions are presented. This study offers novel solutions for the future development of smart wearable devices.

Colocalization of protein and microRNA markers reveals unique extracellular vesicle subpopulations for early cancer detection.

Extracellular vesicles (EVs) play important roles in cell-cell communication but are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm with very limited amounts of cargos encapsulated. The technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) reported in the present work permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, thus enables colocalization assessment for selected protein and microRNA (miRNA) markers in the EVs produced by various cell lines, or present in clinical sera samples. EV subpopulations marked by the colocalization of unique protein and miRNA combinations were discovered to be able to detect early-stage (stage I or II) breast cancer (BC). NOBEL-SPA can be adapted to analyze other types of cargo molecules or other small submicron biological particles. Study of the sorting of specific cargos to heterogeneous vesicles under different physiological conditions can help discover distinct vesicle subpopulations valuable in clinical examination and therapeutics development and gain better understanding of their biogenesis.

Characterization of hypoxia-responsive states in ovarian cancer to identify hot tumors and aid adjuvant therapy.

BACKGROUNDS: The hypoxia-responsive state of cancer is a complex pathophysiological process involving numerous genes playing different roles. Due to the rapid proliferation of cancer cells and chaotic angiogenesis, the clinical features of hypoxia-responsive states are not yet clear in patients with ovarian cancer. METHODS: Based on the RNA expression levels of 14 hypoxic markers, our study screened out hypoxia-related genes and construct a hypoxic score pattern to quantify the hypoxia-responsive states of a single tumor. Combining clinical prognosis, tumor mutation burden, microsatellite instability, the expression level of the immune checkpoint, IC50, and other indicators to evaluate the impact of different hypoxia-responsive states on clinical prognosis and therapeutic sensitivity. RESULTS: Our study identified a subgroup with an active hypoxia-responsive state and they have a worse clinical prognosis but exhibit higher immunogenicity and higher sensitivity to immunotherapy. CONCLUSIONS: This work revealed that hypoxia-responsive states played an important role in formation of tumor immunogenicity. Evaluating the hypoxia-responsive state will contribute to guiding more effective immunotherapy strategies.

Lung Fibroblasts Take up Breast Cancer Cell-derived Extracellular Vesicles Partially Through MEK2-dependent Macropinocytosis.

Extracellular vesicles (EV) have emerged as critical effectors in the cross-talk between cancer and normal cells by transferring intracellular materials between adjacent or distant cells. Previous studies have begun to elucidate how cancer cells, by secreting EVs, adapt normal cells at a metastatic site to facilitate cancer cell metastasis. In this study, we utilized a high-content microscopic screening platform to investigate the mechanisms of EV uptake by primary lung fibroblasts. A selected library containing 90 FDA-approved anticancer drugs was screened for the effect on fibroblast uptake of EVs from MDA-MB-231 breast cancer cells. Among the drugs identified to inhibit EV uptake without exerting significant cytotoxicity, we validated the dose-dependent effect of Trametinib (a MEK1/2 inhibitor) and Copanlisib (a PI3K inhibitor). Trametinib suppressed macropinocytosis in lung fibroblasts and inhibited EV uptake with a higher potency comparing with Copanlisib. Gene knockdown and overexpression studies demonstrated that uptake of MDA-MB-231 EVs by lung fibroblasts required MEK2. These findings provide important insights into the mechanisms underlying lung fibroblast uptake of breast cancer cell-derived EVs, which could play a role in breast cancer metastasis to the lungs and suggest potential therapeutic targets for preventing or treating this deadly disease. SIGNIFICANCE: Through a phenotypic screen, we found that MEK inhibitor Trametinib suppressed EV uptake and macropinocytosis in lung fibroblasts, and that EV uptake is mediated by MEK2 in these cells. Our results suggest that MEK2 inhibition could serve as a strategy to block cancer EV uptake by lung fibroblasts.

Non-Equilibrium Assembly of Atomically-Precise Copper Nanoclusters.

Accurate structure control in dissipative assemblies (DSAs) is vital for precise biological functions. However, accuracy and functionality of artificial DSAs are far from this objective. Herein, a novel approach is introduced by harnessing complex chemical reaction networks rooted in coordination chemistry to create atomically-precise copper nanoclusters (CuNCs), specifically Cu11(µ9-Cl)(µ3-Cl)3L6Cl (L = 4-methyl-piperazine-1-carbodithioate). Cu(I)-ligand ratio change and dynamic Cu(I)-Cu(I) metallophilic/coordination interactions enable the reorganization of CuNCs into metastable CuL2, finally converting into equilibrium [CuL·Y]Cl (Y = MeCN/H2O) via Cu(I) oxidation/reorganization and ligand exchange process. Upon adding ascorbic acid (AA), the system goes further dissipative cycles. It is observed that the encapsulated/bridging halide ions exert subtle influence on the optical properties of CuNCs and topological changes of polymeric networks when integrating CuNCs as crosslink sites. CuNCs duration/switch period could be controlled by varying the ions, AA concentration, O2 pressure and pH. Cu(I)-Cu(I) metallophilic and coordination interactions provide a versatile toolbox for designing delicate life-like materials, paving the way for DSAs with precise structures and functionalities. Furthermore, CuNCs can be employed as modular units within polymers for materials mechanics or functionalization studies.

Recent development of manganese dioxide-based materials as zinc-ion battery cathode.

The development of advanced cathode materials for zinc-ion batteries (ZIBs) is a critical step in building large-scale green energy conversion and storage systems in the future. Manganese dioxide is one of the most well-studied cathode materials for zinc-ion batteries due to its wide range of crystal forms, cost-effectiveness, and well-established synthesis processes. This review describes the recent research progress of manganese dioxide-based ZIBs, and the reaction mechanism, electrochemical performance, and challenges of manganese dioxide-based ZIBs materials are systematically introduced. Optimization strategies for high-performance manganese dioxide-based materials for ZIBs with different crystal forms, nanostructures, morphologies, and compositions are discussed. Finally, the current challenges and future research directions of manganese dioxide-based cathodes in ZIBs are envisaged.

CXCL10 and Nrf2-upregulated mesenchymal stem cells reinvigorate T lymphocytes for combating glioblastoma.

BACKGROUND: Lack of tumor-infiltrating T lymphocytes and concurrent T-cell dysfunction have been identified as major contributors to glioblastoma (GBM) immunotherapy resistance. Upregulating CXCL10 in the tumor microenvironment (TME) is a promising immunotherapeutic approach that potentially increases tumor-infiltrating T cells and boosts T-cell activity but is lacking effective delivery methods. METHODS: In this study, mesenchymal stem cells (MSCs) were transduced with a recombinant lentivirus encoding Cxcl10, Nrf2 (an anti-apoptosis gene), and a ferritin heavy chain (Fth) reporter gene in order to increase their CXCL10 secretion, TME survival, and MRI visibility. Using FTH-MRI guidance, these cells were injected into the tumor periphery of orthotopic GL261 and CT2A GBMs in mice. Combination therapy consisting of CXCL10-Nrf2-FTH-MSC transplantation together with immune checkpoint blockade (ICB) was also performed for CT2A GBMs. Thereafter, in vivo and serial MRI, survival analysis, and histology examinations were conducted to assess the treatments' efficacy and mechanism. RESULTS: CXCL10-Nrf2-FTH-MSCs exhibit enhanced T lymphocyte recruitment, oxidative stress tolerance, and iron accumulation. Under in vivo FTH-MRI guidance and monitoring, peritumoral transplantation of CXCL10-Nrf2-FTH-MSCs remarkably inhibited orthotopic GL261 and CT2A tumor growth in C57BL6 mice and prolonged animal survival. While ICB alone demonstrated no therapeutic impact, CXCL10-Nrf2-FTH-MSC transplantation combined with ICB demonstrated an enhanced anticancer effect for CT2A GBMs compared with transplanting it alone. Histology revealed that peritumorally injected CXCL10-Nrf2-FTH-MSCs survived longer in the TME, increased CXCL10 production, and ultimately remodeled the TME by increasing CD8+ T cells, interferon-γ+ cytotoxic T lymphocytes (CTLs), GzmB+ CTLs, and Th1 cells while reducing regulatory T cells (Tregs), exhausted CD8+ and exhausted CD4+ T cells. CONCLUSIONS: MRI-guided peritumoral administration of CXCL10 and Nrf2-overexpressed MSCs can significantly limit GBM growth by revitalizing T lymphocytes within TME. The combination application of CXCL10-Nrf2-FTH-MSC transplantation and ICB therapy presents a potentially effective approach to treating GBM.

Modified intraoperative temperature management prevents prolonged length of stay after head and neck surgery with free flap reconstruction.

The present study aimed to investigate the association between intraoperative body temperature and prolonged length of stay (PLOS) after free flap reconstruction. A total of 753 patients who underwent head and neck surgery with free flap reconstruction were collected and randomly assigned into primary and validation cohorts. In the primary cohort, univariable and multivariable analyses were conducted to evaluate associations between intraoperative time-weighted (TW) temperature (TW average [TWA] temperature, TW hypothermia and TW hyperthermia) and PLOS. Nomograms were developed with and without intraoperative TW temperature, and validated in the validation cohort. Severe intraoperative TW hypothermia (OR = 1.004; 95% CI: 1.000, 1.007; p = 0.032) was identified as an independent risk factor for PLOS. Intraoperative TWA temperature and TW hypothermia showed linear related predictive effect for PLOS. The nomogram incorporating intraoperative TW temperature showed higher C-index (0.652, 95% CI: 0.591, 0.713) and improved net reclassification improvement for non-event (0.277, 95% CI: 0.118, 0.435; p < 0.001). Lower TWA temperature with mild TW hypothermia had a preventive effect on PLOS with a linear association, which may provide a modified range for intraoperative temperature management. The proposed nomogram incorporating intraoperative TW temperature could be used to develop personalized preventive strategies for PLOS after free flap reconstruction. IRB NUMBER: SYSEC-KY-KS-2022-037. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable.

Preoperative flurbiprofen diminishes the rate of reoperation after free flap reconstruction: A retrospective study.

This study aimed to evaluate the association between preoperative flurbiprofen, a non-selective COX inhibitor, and reoperation for flap crisis after free flap reconstruction. In this retrospective study, patients who underwent head and neck surgery with free flap reconstructions were collected. To identify risk factors for reoperation from demographic features and perioperative variables, univariate and multivariate logistic analyses were conducted. After propensity score matching (PSM), univariate and adjusted multivariate analyses were employed to explore the impact of preoperative flurbiprofen on reoperation after free flap reconstruction. This study comprised 437 patients, 33 of whom underwent reoperations for flap crisis. After multivariate analysis, radiotherapy history (P = 0.005; odds ratio [OR] = 0.225; 95% CI, 0.080-0.636) and preoperative flurbiprofen (P = 0.038; OR = 5.059; 95% CI, 1.094-23.386) were identified as independent factors for reoperation. PSM was achieved, and preoperative flurbiprofen was found to diminish the reoperation rate (P = 0.046; OR = 4.765; 95% CI, 1.029-22.202) without increasing bleeding complications. Within the limitations of the study, flurbiprofen should be administered preoperatively to reduce the rate of reoperations for flap crisis whenever appropriate.

Flexible In-Ga-Zn-N-O synaptic transistors for ultralow-power neuromorphic computing and EEG-based brain-computer interfaces.

Designing low-power and flexible artificial neural devices with artificial neural networks is a promising avenue for creating brain-computer interfaces (BCIs). Herein, we report the development of flexible In-Ga-Zn-N-O synaptic transistors (FISTs) that can simulate essential and advanced biological neural functions. These FISTs are optimized to achieve ultra-low power consumption under a super-low or even zero channel bias, making them suitable for wearable BCI applications. The effective tunability of synaptic behaviors promotes the realization of associative and non-associative learning, facilitating Covid-19 chest CT edge detection. Importantly, FISTs exhibit high tolerance to long-term exposure under an ambient environment and bending deformation, indicating their suitability for wearable BCI systems. We demonstrate that an array of FISTs can classify vision-evoked EEG signals with up to ∼87.9% and 94.8% recognition accuracy for EMNIST-Digits and MindBigdata, respectively. Thus, FISTs have enormous potential to significantly impact the development of various BCI techniques.

Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle.

Skeletal muscle loss and weakness are associated with bad prognosis and poorer quality of life in cancer patients. Tumor-derived factors have been implicated in muscle dysregulation by inducing cachexia and apoptosis. Here, we show that extracellular vesicles secreted by breast cancer cells impair mitochondrial homeostasis and function in skeletal muscle, leading to decreased mitochondrial content and energy production and increased oxidative stress. Mechanistically, miR-122-5p in cancer-cell-secreted EVs is transferred to myocytes, where it targets the tumor suppressor TP53 to decrease the expression of TP53 target genes involved in mitochondrial regulation, including Tfam, Pgc-1α, Sco2, and 16S rRNA. Restoration of Tp53 in muscle abolishes mitochondrial myopathology in mice carrying breast tumors and partially rescues their impaired running capacity without significantly affecting muscle mass. We conclude that extracellular vesicles from breast cancer cells mediate skeletal muscle mitochondrial dysfunction in cancer and may contribute to muscle weakness in some cancer patients.

Selective activation of AKAP150/TRPV1 in ventrolateral periaqueductal gray GABAergic neurons facilitates conditioned place aversion in male mice.

Aversion refers to feelings of strong dislike or avoidance toward particular stimuli or situations. Aversion can be caused by pain stimuli and has a long-term negative impact on physical and mental health. Aversion can also be caused by drug abuse withdrawal, resulting in people with substance use disorder to relapse. However, the mechanisms underlying aversion remain unclear. The ventrolateral periaqueductal gray (vlPAG) is considered to play a key role in aversive behavior. Our study showed that inhibition of vlPAG GABAergic neurons significantly attenuated the conditioned place aversion (CPA) induced by hindpaw pain pinch or naloxone-precipitated morphine withdrawal. However, activating or inhibiting glutamatergic neurons, or activating GABAergic neurons cannot affect or alter CPA response. AKAP150 protein expression and phosphorylated TRPV1 (p-TRPV1) were significantly upregulated in these two CPA models. In AKAP150flox/flox mice and C57/B6J wild-type mice, cell-type-selective inhibition of AKAP150 in GABAergic neurons in the vlPAG attenuated aversion. However, downregulating AKAP150 in glutamatergic neurons did not attenuate aversion. Knockdown of AKAP150 in GABAergic neurons effectively reversed the p-TRPV1 upregulation in these two CPA models utilized in our study. Collectively, inhibition of the AKAP150/p-TRPV1 pathway in GABAergic neurons in the vlPAG may be considered a potential therapeutic target for the CPA response.

Nomogram incorporating potent inflammatory indicators for overall survival estimation of patients with primary oral squamous cell carcinoma.

Background: Inflammation has been recognized to be a factor that substantially influences tumorigenesis and tumor prognosis. Hence, this study was aimed to investigate an inflammatory marker with the most potent prognostic ability and to evaluate the survival estimation capability of dynamic change in this marker for patients suffered from oral squamous cell carcinoma (OSCC). Methods: 469 patients' inflammatory indicators including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory response index (SIRI), were calculated. Their predictive abilities for overall survival (OS) were evaluated by Kaplan-Meier curves to screen for the one with the most potent prognostic value. The predictive ability of dynamic changes in this marker was verified and a predictive nomogram incorporating inflammatory indicators was developed. Results: A high LMR was identified to be an indicator of a satisfactory survival rate. Compared with that of other inflammatory markers, area under the receiver operating characteristics (ROC) curve (AUC) of LMR for 1-year and 3-year OS was significantly larger (P<0.001). Dynamic LMR change remained an significant parameter for predicting OS (OR: 2.492, 95% CI: 1.246-4.981, p = 0.010). The nomogram incorporating LMR exhibited a superior prognostic significance than the TNM system, as suggested by the C-index (0.776 vs 0.651 in primary cohort; 0.800 vs 0.707 in validation cohort, P<0.001) and AUC. Conclusions: LMR was demonstrated to possess a more potent survival estimation capability than the other three inflammatory parameters. Dynamic changes in LMR serves as a significant parameter for overall survival estimation of primary OSCC patients. The established nomogram incorporating inflammatory markers showed more accuracy and sensitivity for survival estimation of primary OSCC patients.

Altered structural covariance of locus coeruleus in individuals with significant memory concern and patients with mild cognitive impairment.

The locus coeruleus (LC) is the site where tau accumulation is preferentially observed pathologically in Alzheimer's disease (AD) patients, but the changes in gray matter co-alteration patterns between the LC and the whole brain in the predementia phase of AD remain unclear. In this study, we estimated and compared the gray matter volume of the LC and its structural covariance (SC) with the whole brain among 161 normal healthy controls (HCs), 99 individuals with significant memory concern (SMC) and 131 patients with mild cognitive impairment (MCI). We found that SC decreased in MCI groups, which mainly involved the salience network and default mode network. These results imply that seeding from LC, the gray matter network disruption and disconnection appears early in the MCI group. The altered SC network seeding from the LC can serve as an imaging biomarker for discriminating the patients in the potential predementia phase of AD from the normal subjects.