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Abstract The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.

Abstract While protein aggregation’s association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

Accurate mapping between single‐cell RNA sequencing (scRNA‐seq) and low‐resolution spatial transcriptomics (ST) data compensates for both limited resolution of ST data and missing spatial information of scRNA‐seq. Celloc, a method developed for this purpose, incorporates a graph attention autoencoder and comprehensive loss functions to facilitate flexible single cell‐to‐spot mapping. This enables either the dissection of cell composition within each spot or the assignment of spatial locations for every cell in scRNA‐seq data. Celloc's performance is benchmarked on simulated ST data, demonstrating superior accuracy and robustness compared to state‐of‐the‐art methods. Evaluations on real datasets suggest that Celloc can reconstruct cellular spatial structures with various cell types across different tissues and histological regions.

Abstract Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

The carbon sequestration capacity of vegetation is the key to the carbon cycle in terrestrial ecosystems. It is significant to analyze the spatiotemporal variation and influencing factors of vegetation carbon sequestration ability to improve territorial carbon sink and optimize its spatial pattern. However, there is a lack of understanding of the impact of environmental conditions and human activity on the vegetation’s carbon sequestration ability, especially in highly urbanized areas. For example, effective vegetation management methods can enhance vegetation Gross Primary Productivity, while emissions of air pollutants like O3, CO, NO2, and PM2.5 can suppress it. This paper mainly explores the factors influencing vegetation carbon sequestration capacity across different regions of Beijing. Based on remote sensing data and site observation data, this paper analyzed the spatiotemporal variation trend of Annual Gross Primary Production (AGPP) and the influence of environmental factors and human activity factors on GPP in Beijing from 2000 to 2020 by using the Theil−Sen’s slope estimator, Mann−Kendall trend test, and comparing Geographically Weighted Regression method (GWR) and Geographically and Temporally Weighted Regression method (GTWR). GWR is a localized multiple regression technique used to estimate variable relationships that vary spatially. GTWR extends GWR by adding temporal analysis, enabling a comprehensive examination of spatiotemporal data variations. Besides, we used land use cover data to discuss the influence of land use cover change on AGPP. The results showed that the spatial distribution pattern of GPP in Beijing was higher in the northwest and lower in the southeast, and it showed an overall upward trend from 2000 to 2020, with an average annual growth rate of 14.39 g C·m−2·a−1. From 2000 to 2020, excluding the core urban areas, the GPP of 95.8% of Beijing increased, and 10.6% of Beijing showed a trend of significant increase, concentrated in Mentougou, Changping, and Miyun. GPP decreased in 4.1% of the regions in Beijing and decreased significantly in 1.4% of the areas within the sixth ring. The areas where AGPP significantly decreased were concentrated in those where land use types were converted to Residential land (impervious land), while AGPP showed an upward trend in other areas. CO and NO2 are the main driving forces of GPP change in Beijing. O3 and land surface temperature (LST) also exert certain influences, while the impact of precipitation (PRE) is relatively minor. O3 and CO have a positive impact on AGPP as a whole, while LST and NO2 generally exhibit negative impacts. PRE has a positive impact in the central area of Beijing, while it has a negative impact in the peripheral areas. This study further discusses opinions on future urbanization and environmental management policies in Beijing, which will promote the carbon peak and carbon neutrality process of ecological space management in Beijing. Besides, this study was conducted at the urban scale rather than at ecological sites, encompassing a variety of factors that influence vegetation AGPP. Consequently, the results also offer fresh insights into the intricate nexus between human activities, pollutants, and the GPP of vegetation.

Emergency communication networks play a vital role in disaster monitoring, transmission, and application during disaster emergency response (DER), however, the performance and stability of edge nodes in the emergency communication networks are often weak due to limited communication and computation resources. This weakness directly affects the quality of service (QoS) of the geospatial edge service (GES) chains involved in emergency monitoring. Existing research predominantly addresses service compositions in stable environments, neglecting the aggregation of efficient and robust GES chains in emergency communication networks. This study proposes an evolutionary particle swarm optimization (EPSO)-based emergency monitoring GES chain in an emergency communication network. It includes a GES chain model of emergency environment monitoring for tailing areas, as well as the designs of the particle chromosome encoding method, fitness evaluation model, and particle chromosome swarm update operators of the EPSO-based GES chain. Finally, the study conducts emergency environment monitoring experiments for tailing areas using the proposed method. Experiments results demonstrate that the proposed method significantly enhances the efficiency, stability, and reliability of emergency monitoring GES chains in the emergency communication network. This is crucial to providing fast and reliable services for DER during natural disasters.

Deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression, while mechanisms underlying its therapeutic effects remain poorly defined. Increasing evidence has revealed an intimate association between the lateral habenula (LHb) and major depression, and suggests that the LHb might be an effective target of DBS therapy for depression. Here, we found that DBS in the LHb effectively decreased depression-like behaviors in rats experienced with chronic unpredictable mild stress (CUMS), a well-accepted paradigm for modeling depression in rodents. In vivo electrophysiological recording unveiled that CUMS increased neuronal burst firing, as well as the proportion of neurons showing hyperactivity to aversive stimuli in the LHb. Nevertheless, DBS downregulated local field potential power, reversed the CUMS-induced increase of LHb burst firing and neuronal hyperactivity to aversive stimuli, and decreased the coherence between LHb and ventral tegmental area (VTA). Our results demonstrate that DBS in the LHb exerts antidepressant-like effects and reverses local neural hyperactivity, supporting the LHb as a target of DBS therapy for depression.

Summary: Chronic pain is one of the most significant medical problems throughout the world. Recent evidence has confirmed the hippocampus as an active modulator of pain chronicity, but the underlying mechanisms remain unclear. Using in vivo electrophysiology, we identify a neural ensemble in the ventral hippocampal CA1 (vCA1) that shows inhibitory responses to noxious but not innocuous stimuli. Following peripheral inflammation, this ensemble becomes responsive to innocuous stimuli, representing hypersensitivity. Mimicking the inhibition of vCA1 neurons using chemogenetics induces chronic pain-like behaviors in naive mice, whereas activating vCA1 neurons in mice with peripheral inflammation results in a reduction of pain-related behaviors. Pathway-specific manipulation of vCA1 projections to basolateral amygdala (BLA) and infralimbic cortex (IL) shows that these pathways are differentially involved in pain modulation at different temporal stages of chronic inflammatory pain. These results confirm a crucial role of the vCA1 and its circuits in modulating the development of chronic pain.

Community detection can reveal unknown spatial structures embedded in spatial networks. Current spatial community detection methods are mostly modularity-based. However, due to the lack of appropriate spatial networks serving as a benchmark, the accuracy and effectiveness of these methods have not been tested sufficiently so far. This study first introduced a spatial autoregressive and gravity model united method (SARGM) to simulate benchmark spatial networks with known regional distributions. Then, a novel spectral clustering-based spatial community detection method (SCSCD) was proposed to identify spatial communities from eight kinds of benchmark spatial networks. Comparative experiments on SCSCD and three other methods showed that SCSCD performed the best in accuracy and effectiveness. Moreover, the scale parameter and the community number setting of the SCSCD were investigated experimentally. Finally, a case study was applied to the SCSCD to demonstrate its ability to extract the internal community structure of a high-speed train network in China.

Background Multimodal opioid‐sparing analgesia is a key component of an enhanced recovery pathway after surgery that aims to improve postoperative recovery. Transcutaneous electrical acupoint stimulation (TEAS) is assumed to alleviate pain and anxiety and to modify the autonomic nervous system. This study aimed to determine the efficacy of TEAS for sedation and postoperative analgesia in lung cancer patients undergoing thoracoscopic pulmonary resection. Methods A total of 80 patients were randomized into two groups: the TEAS group and the sham TEAS combined with general anesthesia group. Postoperative pain levels at six, 24, 48 hours, and one month after surgery were measured using the visual analogue scale (VAS). Bispectral index (BIS) score during the TEAS prior to anesthetic induction, Observer's Assessment of Alertness/Sedation (OAAS) score, sufentanil consumption during postoperative patient‐controlled intravenous analgesia (PCIA), number of total and effective attempts of PCIA pump use, and incidence of postoperative nausea and vomiting were recorded and analyzed statistically. Results Patients in the TEAS group had significantly lower VAS scores at six, 24, and 48 hours after surgery (P

The CRISPR-Cas9 enables efficient gene editing in various cell types, including post-mitotic neurons. However, neuronal ensembles in the same brain region can still be functionally or anatomically different, and such heterogeneity requires gene editing in specific neuronal populations. We recently developed a CRISPR-SaCas9 system-based technique. Combined with activity-dependent cell-labeling methods and anterograde/retrograde adeno-associated virus (AAV) vectors, this technique achieves function- and projection-specific gene editing in the mammalian brain. We showed that perturbing cbp (CREB-binding protein) in extinction-ensemble neurons among amygdala-projecting infralimbic cortex (IL) cells impaired fear extinction learning, demonstrating the high efficiency in regulation of extinction learning with CRISPR-Cas9. Here, we describe a detailed protocol of gene perturbation in presynaptic extinction-ensemble neurons in adult rats, including gRNA design, gRNA evaluation in vitro, stereotaxic AAV injection, and contextual fear conditioning. The high specificity and efficiency of projection- and function-specific CRISPR-SaCas9 system can be widely applied in neural circuitry studies.

A transparent and penetrable cranial window is essential for neuroimaging, transcranial injection and comprehensive understanding of cortical functions. For these applications, cranial windows made from glass coverslip, polydimethylsiloxane (PDMS), polymethylmethacrylate, crystal and silicone hydrogel have offered remarkable convenience. However, there is a lack of high-strength, high-transparency, penetrable cranial window with clinical application potential. We engineer high-strength hybrid Titanium-PDMS (Ti-PDMS) cranial windows, which allow large transparent area for in vivo two-photon imaging, and provide a soft window for transcranial injection. Laser scanning and 3D printing techniques are used to match the hybrid cranial window to different skull morphology. A multi-cycle degassing pouring process ensures a good combination of PDMS and Ti frame. Ti-PDMS cranial windows have a high fracture strength matching human skull bone, excellent light transmittance up to 94.4%, and refractive index close to biological tissue. Ti-PDMS cranial windows show excellent bio-compatibility during 21-week implantation in mice. Dye injection shows that the PDMS window has a “self-sealing” to keep liquid from leaking out. Two-photon imaging for brain tissues could be achieved up to 450 µm in z-depth. As a novel brain-computer-interface, this Ti-PDMS device offers an alternative choice for in vivo drug delivery, optical experiments, ultrasonic treatment and electrophysiology recording.

Pain medicine: Boosting the potency of opioid analgesics A hormone known to weaken the pain-relieving effects of opioid drugs does so because of interaction between the hormone receptor and the opioid receptor. A team from Peking University in Beijing, China, led by Li Su and You Wan showed that an opioid receptor and a receptor that is activated by a peptide hormone involved in digestion are both found in rat neurons of the spinal cord and spinal ganglion. They demonstrated in human cells that the two receptors could form a single structural complex, and that this process weakened the ability of the opioid receptor to respond to drugs such as morphine. A decoy peptide that disrupted the interaction between the receptors boosted the analgesic effects of morphine in rats. Similar strategies could help with pain management.

Extracellular electrophysiology has been widely applied in neural network studies. Local field potentials and single-unit activities can be recorded with high-density electrodes, which facilitate the decoding of neural codes. However, the chronic multi-regional recording is still a challenging task for achieving high placement accuracy and long-term stability. Here, we present a novel electrode design with low-cost 3D-printed parts and custom printed circuits boards. This new design could facilitate precise electrode placement in multiple brain regions simultaneously and reduce the working time for surgical procedures as well. In this paper, the design and fabrication of the 3D printed multi-channel microdrive are explained in detail. We also show the result of high-quality electrophysiological recordings in eight pain-related areas from rats and the electrode placement accuracy. This novel 3D-printed multi-drive system could achieve synchronous electrophysiological recording in multiple brain regions and facilitate future neural network research.

Summary: Pain involves an intrinsically dynamic connectome characterized by fluctuating spontaneous brain activity and continuous neuroplastic changes of relevant circuits. Activity in the hippocampus-medial prefrontal cortex (mPFC) pathway has been suggested to correlate with spontaneous pain and pain chronicity, but causal evidence is lacking. Here we combine longitudinal in vivo electrophysiological recording with behavioral testing and show that persistent spontaneous pain disrupts ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with peripheral inflammation. Chemo- and optogenetic rescue of vCA1-IL dysfunction relieves spontaneous pain. Circuit-specific overexpression of brain-derived neurotrophic factor (BDNF) in vCA1-IL reverses electrophysiological changes, relieves spontaneous pain, and accelerates overall recovery from inflammatory pain. Our work identifies a neural pathway that specifically correlates with spontaneous pain and supports the significance of using a circuit dynamics-based strategy for more comprehensive understanding of circuitry mechanisms underlying chronic pain. : Ma et al. show that persistent spontaneous pain disrupts ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity in rats with peripheral inflammation. Genetic rescue of vCA1-IL dysfunction relieves spontaneous pain and accelerates overall pain recovery. This work identifies a neural pathway that specifically correlates with spontaneous pain. Keywords: hippocampus, prefrontal cortex, pain, electrophysiology, inflammation

In acute and ongoing pain, the spontaneous oscillatory activity of electroencephalogram (EEG) has been characterized by suppression of alpha band oscillations and enhancement of gamma band oscillations. In pathological chronic pain which is more severe and common in clinic practice, it is of great interest to investigate the oscillatory activity especially at the broad gamma frequency bands. Our present study explored the resting state oscillatory activities of EEG in patients with post-herpetic neuralgia (PHN) over 3 months which is a typical neuropathic pain model in clinical researches. It was found that the PHN patients showed anxiety and depression revealed by Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) examinations. Power spectrum analysis revealed that the power at gamma frequency band (from 40 to 70 Hz) of EEG was significantly higher in the PHN patients, and positively correlated with pain intensity, anxiety, and depression indexes. Further, increased gamma activity derived from the prefrontal cortex and the cerebellum were revealed by cluster-based sensor level and the beamforming source level analyses. These results suggest the enhanced gamma oscillatory activity in the prefrontal cortex and cerebellum is a characteristic marker in chronic neuropathic pain patients.

Chronic cerebral hypoperfusion is one of the fundamental pathological causes of brain disease such as vascular dementia. Exploration of effective treatments for this is of great interest. Histidine has been reported to be effective in anti-apoptosis, antioxidant, and against excitotoxicity. In the present study, we aim to investigate whether histidine could have a therapeutic effect on the impairments induced by chronic cerebral hypoperfusion. Cerebral hypoperfusion model was established through bilateral common carotid arteries stenosis (BCAS) operation in Tie2-GFP mice. Radial arm maze and Morris water maze revealed that histidine showed potential improvement of the tendency of cognitive impairments induced by hypoperfusion. The possible mechanisms were further investigated. After administration of histidine in hypoperfusion mice, immunofluorescent BrdU staining revealed more new-born nerve cells. In vivo observation through a cranial window under two-photon laser-scanning microscopy demonstrated that the blood flow velocity in capillary was improved, the distance between the astrocytes and the penetrating artery was shortened. Histidine administration also significantly increased the protein expression level of zonula occludens protein 1, an indicator of the integrity of blood–brain barrier (BBB). These results suggest that histidine could alleviate the impairments induced by chronic cerebral hypoperfusion in mice, and this effect may be related to the neurogenesis, astrocytes, and the integrity of the BBB.

Previous experience of chronic pain causes enhanced responses to upcoming noxious events in both humans and animals, but the underlying mechanisms remain unclear. In the present study, we found that rats with complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain experience exhibited aggravated pain responses to later formalin test. Enhanced neuronal activation upon formalin assaults and increased phosphorylated cAMP-response element binding protein (CREB) were observed in the prelimbic cortex (PL) of rats with chronic inflammatory pain experience, and inhibiting PL neuronal activities reversed the aggravated pain. Inflammatory pain experience induced persistent p38 mitogen-activated protein kinase (MAPK; p38) but not extracellular regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) hyperphosphorylation in the PL. Inhibiting the p38 phosphorylation in PL reversed the aggravated nociceptive responses to formalin test and down-regulated enhanced phosphorylated CREB in the PL. Chemogenetics identified PL–periaqueductal gray (PAG) but not PL–nucleus accumbens (NAc) as a key pathway in inducing the aggravated formalin pain. Our results demonstrate that persistent hyperphosphorylation of p38 in the PL underlies aggravated nociceptive responses in rats with chronic inflammatory pain experience.

Injuries to peripheral nerve fibers induce neuropathic pain. But the involvement of adjacent uninjured fibers to pain is not fully understood. The present study aims to investigate the possible contribution of Cav3.2 T-type calcium channels in uninjured afferent nerve fibers to neuropathic pain in rats with spared nerve injury (SNI). Aβ-, Aδ- and C-fibers of the uninjured sural nerve were sensitized revealed by in vivo single-unit recording, which were accompanied by accumulation of Cav3.2 T-type calcium channel proteins shown by Western blotting. Application of mibefradil, a T-type calcium channel blocker, to sural nerve receptive fields increased mechanical thresholds of Aβ-, Aδ- and C-fibers, confirming the functional involvement of accumulated channels in the sural nerve in SNI rats. Finally, perineural application of mibefradil or TTA-P2 to the uninjured sural nerve alleviated mechanical allodynia in SNI rats. These results suggest that axonal accumulation of Cav3.2 T-type calcium channels plays an important role in the uninjured sural nerve sensitization and contributes to neuropathic pain.

The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury.

Acupuncture, as a healing art in traditional Chinese medicine, has been widely used to treat various diseases. In the history of acupuncture anesthesia, in the past decades, mechanisms of acupuncture analgesia has been widely investigated, and in recent years, acupuncture protection on organ functions has attracted great interest. This review summarized the research progress on mechanisms of acupuncture for analgesia and its protection against organ function injury in anesthesia, and its perspective of analgesia, immunomodulation, neuroendocrine regulation and multiple organ protection. The current evidence supports that acupuncture analgesia and its organ protection in anesthesia is associated with the integration of neuroendocrine-immune networks in the level of neurotransmitters, cytokines, hormones, neuronal ensembles, lymphocytes, and endocrine cells. Although the mechanisms of acupuncture analgesia and its organ protection are still not completely understood, basic as well as clinic researches on the mechanisms and applications of acupuncture and related techniques are being carried out.

Previous studies have shown that multiple brain regions are involved in pain perception and pain-related neural processes by forming a functionally connected pain network. It is still unclear how these pain-related brain areas actively work together to generate the experience of pain. To get a better insight into the pain network, we implanted electrodes in four pain-related areas of rats including the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), primary somatosensory cortex (S1) and periaqueductal gray (PAG). We analyzed the pattern of local field potential (LFP) oscillations under noxious laser stimulations and innoxious laser stimulations. A high-dimensional feature matrix was built based on the LFP characters for both experimental conditions. Generalized linear models (GLMs) were trained to classify recorded LFPs under noxious vs. innoxious condition. We found a general power decrease in α and β bands and power increase in γ band in the recorded areas under noxious condition. After noxious laser stimulation, there was a consistent change in LFP power and correlation in all four brain areas among all 13 rats. With GLM classifiers, noxious laser trials were distinguished from innoxious laser trials with high accuracy (86%) using high-dimensional LFP features. This work provides a basis for further research to examine which aspects (e.g., sensory, motor or affective processes) of noxious stimulation should drive distinct neural activity across the pain network.

Chronic pain is a pathological developing course of pain. In clinic, an objective indicator is needed for diagnosing and better controlling chronic pain. The abnormal neural responses in chronic pain are reflected by multiple event-related potentials (ERPs) in time, frequency, and location domain, respectively. However, multiple changes in ERPs are not applicable in clinic. So, the principal feature covered the most informative changes extracted from these three domains of ERP during the development of chronic pain is needed. In the present study, a parallel factor analysis method was employed to extract time–frequency–channel features of laser-evoked potential (LEP) simultaneously from rats with chronic inflammatory pain. Results showed that the main feature of LEP in channel domain locates in the frontal brain region in rats with chronic inflammatory pain while in the parietal brain region in control rats. In the frequency domain, the main frequency of LEP was significantly higher in chronic inflammatory pain rats than that in control rats. These findings indicate that the frontal region with higher frequency response to nociceptive information is the principal feature in the chronic pain state. Our study provided not only a principal feature of LEP but also a promising strategy for chronic pain, which is potential for clinic application.

It has been reported that oscillatory gamma activity participates in brief acute pain and tonic ongoing pain. It is of great interest to determine whether the gamma activity is involved in chronic pain since chronic pain is a more severe pathological condition characterized by pain persistency. To investigate the oscillatory gamma activity in chronic pain, in the present study, we recorded spontaneous electrocorticogram (ECoG) signals during chronic pain development in rats with chronic inflammatory pain induced by monoarthritis. Power spectrum analysis of ECoG data showed that gamma power increased significantly at the late stage of chronic inflammatory pain. The increased gamma activity occurred mainly at electrodes over primary somatosensory cortices. In rats with chronic pain, the gamma power was positively correlated with the hyperalgesia measured by laser energy that elicited hindpaw withdrawal response. Furthermore, an increased coupling between the amplitude of gamma power and the phase of theta oscillations was observed in chronic inflammatory pain condition. These results indicate an enhanced spontaneous gamma activity in chronic pain and suggest a potential biomarker for the severity of chronic pain.

Housing is among the most pressing issues in urban China and has received considerable scholarly attention. Researchers have primarily concentrated on identifying the factors that influence residential property prices and how such mechanisms function. However, few studies have examined the potential factors that influence housing prices from a big data perspective. In this article, we use a big data perspective to determine the willingness of buyers to pay for various factors. The opinions and geographical preferences of individuals for places can be represented by visit frequencies given different motivations. Check-in data from the social media platform Sina Visitor System is used in this article. Here, we use kernel density estimation (KDE) to analyse the spatial patterns of check-in spots (or places of interest, POIs) and employ the Getis-Ord [Formula: see text] method to identify the hot spots for different types of POIs in Shenzhen, China. New indexes are then proposed based on the hot-spot results as measured by check-in data to analyse the effects of these locations on housing prices. This modelling is performed using the hedonic price method (HPM) and the geographically weighted regression (GWR) method. The results show that the degree of clustering of POIs has a significant influence on housing values. Meanwhile, the GWR method has a better interpretive capacity than does the HPM because of the former method's ability to capture spatial heterogeneity. This article integrates big social media data to expand the scope (new study content) and depth (study scale) of housing price research to an unprecedented degree.

Existing spatial community detection algorithms are usually modularity based. Motivated by different applications, these algorithms build appropriate spatial null models to describe spatial effects on the connection of nodes. Then, by choosing certain modularity maximizing strategies, they try to find interesting community structures hidden behind the null models. In this paper, a novel structural similarity-based spatial network community is defined, which is based on the shared neighbors of nodes. In addition, there are two other special node roles defined: the spatial hub and outlier. Then, a density and adjacency expansion-based spatial structural community detection algorithm for networks (DASSCAN) is proposed for mining these communities, hubs and outliers. DASSCAN uses structural similarity to measure the relationship between nodes, and then, structurally similar and spatially adjacent nodes are merged into communities using a density-based clustering method and spatial adjacency expansion strategy. Comparative experiments on two kinds of Chinese train line networks clarified the accuracy and efficiency of DASSCAN in finding the spatial structural communities, spatial hubs and outliers. The communities found can be used to uncover more interesting spatial structural patterns, and the hubs and outliers are more accurate and have more valuable meanings.

Trajectory pattern mining is becoming increasingly popular because of the development of ubiquitous computing technology. Trajectory data contain abundant semantic and geographic information that reflects people’s movement patterns, i.e., who is performing a certain type of activity when and where. However, the variety and complexity of people’s movement activity and the large size of trajectory datasets make it difficult to mine valuable trajectory patterns. Moreover, most existing trajectory similarity measurements only consider a portion of the information contained in trajectory data. The patterns obtained cannot be interpreted well in terms of both semantic meaning and geographic distributions. As a result, these patterns cannot be used accurately for recommendation systems or other applications. This paper introduces a novel concept of the semantic-geographic pattern that considers both semantic and geographic meaning simultaneously. A flexible density-based clustering algorithm with a new trajectory similarity measurement called semantic intensity is used to mine these semantic-geographic patterns. Comparative experiments on check-in data from the Sina Weibo service demonstrate that semantic intensity can effectively measure both semantic and geographic similarities among trajectories. The resulting patterns are more accurate and easy to interpret.

We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin-resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain.

BackgroundChronicity of pain is one of the most interesting questions in chronic pain study. Clinical and experimental data suggest that supraspinal areas responsible for negative emotions such as depression and anxiety contribute to the chronicity of pain. The amygdala is suspected to be a potential structure for the pain chronicity due to its critical role in processing negative emotions and pain information.ObjectiveThis study aimed to investigate whether amygdala or its subregions, the basolateral amygdala (BLA) and the central medial amygdala (CeA), contributes to the pain chronicity in the spared nerve injury (SNI)-induced neuropathic pain model of rats.Methodology/principal findings(1) Before the establishment of the SNI-induced neuropathic pain model of rats, lesion of the amygdaloid complex with stereotaxic injection of ibotenic acid (IBO) alleviated mechanical allodynia significantly at days 7 and 14, even no mechanical allodynia at day 28 after SNI; Lesion of the BLA, but not the CeA had similar effects; (2) however, 7 days after SNI when the neuropathic pain model was established, lesion of the amygdala complex or the BLA or the CeA, mechanical allodynia was not affected.ConclusionThese results suggest that BLA activities in the early stage after nerve injury might be crucial to the development of pain chronicity, and amygdala-related negative emotions and pain-related memories could promote pain chronicity.

BACKGROUND: Bone cancer pain seriously affects the quality of life of cancer patients. Our previous study found that endogenous formaldehyde was produced by cancer cells metastasized into bone marrows and played an important role in bone cancer pain. However, the mechanism of production of this endogenous formaldehyde by metastatic cancer cells was unknown in bone cancer pain rats. Lysine-specific demethylase 1 (LSD1) is one of the major enzymes catalyzing the production of formaldehyde. The expression of LSD1 and the concentration of formaldehyde were up-regulated in many high-risk tumors. OBJECTIVE: This study aimed to investigate whether LSD1 in metastasized MRMT-1 breast cancer cells in bone marrows participated in the production of endogenous formaldehyde in bone cancer pain rats. METHODOLOGY/PRINCIPAL FINDINGS: Concentration of the endogenous formaldehyde was measured by high performance liquid chromatography (HPLC). Endogenous formaldehyde dramatically increased in cultured MRMT-1 breast cancer cells in vitro, in bone marrows and sera of bone cancer pain rats, in tumor tissues and sera of MRMT-1 subcutaneous vaccination model rats in vivo. Formaldehyde at a concentration as low as the above measured (3 mM) induced pain behaviors in normal rats. The expression of LSD1 which mainly located in nuclei of cancer cells significantly increased in bone marrows of bone cancer pain rats from 14 d to 21 d after inoculation. Furthermore, inhibition of LSD1 decreased the production of formaldehyde in MRMT-1 cells in vitro. Intraperitoneal injection of LSD1 inhibitor pargyline from 3 d to 14 d after inoculation of MRMT-1 cancer cells reduced bone cancer pain behaviors. CONCLUSION: Our data in the present study, combing our previous report, suggested that in the endogenous formaldehyde-induced pain in bone cancer pain rats, LSD1 in metastasized cancer cells contributed to the production of the endogenous formaldehyde.

BACKGROUND: There is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment. METHODOLOGY/PRINCIPAL FINDINGS: Endogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1 approximately 5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of [Ca(2+)]i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses. CONCLUSIONS/SIGNIFICANCE: Our data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment.

Abstract Background Increasing experimental and clinical data indicate that early brain injury (EBI) after subarachnoid hemorrhage (SAH) largely contributes to unfavorable outcomes, and it has been proved that EBI following SAH is closely associated with oxidative stress and brain edema. The present study aimed to examine the effect of hydrogen, a mild and selective cytotoxic oxygen radical scavenger, on oxidative stress injury, brain edema and neurology outcome following experimental SAH in rabbits. Results The level of MDA, caspase-12/3 and brain water content increased significantly at 72 hours after experimental SAH. Correspondingly, obvious brain injury was found in the SAH group by terminal deoxynucleotidyl transferase-mediated uridine 5’-triphosphate-biotin nick end-labeling (TUNEL) and Nissl staining. Similar results were found in the SAH + saline group. In contrast, the upregulated level of MDA, caspase-12/3 and brain edema was attenuated and the brain injury was substantially alleviated in the hydrogen treated rabbits, but the improvement of neurology outcome was not obvious. Conclusion The results suggest that treatment with hydrogen in experimental SAH rabbits could alleviate brain injury via decreasing the oxidative stress injury and brain edema. Hence, we conclude that hydrogen possesses the potential to be a novel therapeutic agent for EBI after SAH.

Abstract Understanding the genetic basis of developmental delay (DD) and intellectual disability (ID) remains a considerable clinical challenge. This study evaluated the clinical application of trio whole exome sequencing (WES) in children diagnosed with DD/ID. The study comprised 173 children with unexplained DD/ID. The participants underwent trio-WES and their demographic, clinical, and genetic characteristics were evaluated. Based on their clinical features, the participants were classified into two groups for further analysis: a syndromic DD/ID group and a non-syndromic DD/ID group. The genetic diagnostic yield of the 173 children diagnosed with DD/ID was 49.7% (86/173). This included 58 pathogenic or likely pathogenic single nucleotide variants (SNVs) in 41 genes identified across 54 individuals (31.2%) through trio-WES. Among these, 22 SNVs had not been previously reported. Additionally, 30 copy number variations (CNVs) were detected in 36 individuals (20.8%). The diagnostic yield in the syndromic DD/ID group was higher than that in the non-syndromic DD/ID group (57.8% vs. 47.2%, P