Non-small cell lung cancer (NSCLC) is a well-known global health concern. TFAP4 has been reported to function as an oncogene. This study sought to investigate the molecular mechanism of TFAP4 in NSCLC development. Significantly highly-expressed gene IGF2BP1 was screened on online databases and its downstream gene TK1 was predicted. IGF2BP1 promoter sequence was identified. The binding site of TFAP4 and IGF2BP1 was predicted. The expression correlations among TFAP4, IGF2BP1, and TK1 were confirmed. The correlations between TFAP4, IGF2BP1, TK1, and NSCLC prognosis were predicted. NSCLC and paracancerous tissues were collected. The expressions of TFAP4, IGF2BP1, and TK1 were detected. NSCLC cell proliferation, migration, invasion, and apoptosis were detected. The binding of TFAP4 to the IGF2BP1 promoter was verified. m6A modification of TK1 mRNA was detected. The correlation between IGF2BP1 and TK1 was confirmed. A subcutaneous tumor xenograft model was established to validate the effect of TFAP4 in vivo. IGF2BP1 was highly expressed in NSCLC tissues and cells. IGF2BP1 knockdown repressed NSCLC cell proliferation, migration, and invasion and facilitated apoptosis. Mechanically, TFAP4 transcriptionally activated IGF2BP1. IGF2BP1 stabilized TK1 expression via m6A modification and promoted NSCLC cell proliferation, migration, and invasion. In vivo experiments confirmed that TFAP4 knockdown suppressed tumor growth by downregulating IGF2BP1/TK1.

Head direction (HD) cells form a fundamental component in the brain's spatial navigation system and are intricately linked to spatial memory and cognition. Although HD cells have been shown to act as an internal neuronal compass in various cortical and subcortical regions, the neural substrate of HD cells is incompletely understood. It is reported that HD cells in the somatosensory cortex comprise regular-spiking (RS, putative excitatory) and fast-spiking (FS, putative inhibitory) neurons. Surprisingly, somatosensory FS HD cells fire in bursts and display much sharper head-directionality than RS HD cells. These FS HD cells are nonconjunctive, rarely theta rhythmic, sparsely connected and enriched in layer 5. Moreover, sharply tuned FS HD cells, in contrast with RS HD cells, maintain stable tuning in darkness; FS HD cells' coexistence with RS HD cells and angular head velocity (AHV) cells in a layer-specific fashion through the somatosensory cortex presents a previously unreported configuration of spatial representation in the neocortex. Together, these findings challenge the notion that FS interneurons are weakly tuned to sensory stimuli, and offer a local circuit organization relevant to the generation and transmission of HD signaling in the brain.

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

Thrombopoietin (TPO) is a haematopoietic cytokine mainly produced by the liver and kidneys, which stimulates the production and maturation of megakaryocytes. In the past decade, numerous studies have investigated the effects of TPO outside the haematopoietic system; however, the role of TPO in the progression of solid cancer, particularly lung cancer, has not been well studied. Exogenous TPO does not affect non-small-cell lung cancer (NSCLC) cells as these cells show no or extremely low TPO receptor expression; therefore, in this study, we focused on endogenous TPO produced by NSCLC cells. Immunohistochemical analysis of 150 paired NSCLC and adjacent normal tissues indicated that TPO was highly expressed in NSCLC tissues and correlated with clinicopathological parameters including differentiation, P-TNM stage, lymph node metastasis and tumour size. Suppressing endogenous TPO by small interfering RNA inhibited the proliferation and migration of NSCLC cells. Moreover, TPO interacted with the EGFR protein and delayed ligand-induced EGFR degradation, thus enhancing EGFR signalling. Notably, overexpressing TPO in EGF-stimulated NSCLC cells facilitated cell proliferation and migration, whereas no obvious changes were observed without EGF stimulation. Our results suggest that endogenous TPO promotes tumorigenicity of NSCLC via regulating EGFR signalling and thus could be a therapeutic target for treating NSCLC.

Advances in human neuroimaging has enabled us to study functional connections among various brain regions in pain states. Despite a wealth of studies at high anatomic resolution, the exact neural signals for the timing of pain remain little known. Identifying the onset of pain signals from distributed cortical circuits may reveal the temporal dynamics of pain responses and subsequently provide important feedback for closed-loop neuromodulation for pain.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

The prefrontal cortex (PFC) plays a prominent role in performing flexible cognitive functions and working memory, yet the underlying computational principle remains poorly understood. Here, we trained a rate-based recurrent neural network (RNN) to explore how the context rules are encoded, maintained across seconds-long mnemonic delay, and subsequently used in a context-dependent decision-making task. The trained networks replicated key experimentally observed features in the PFC of rodent and monkey experiments, such as mixed selectivity, neuronal sequential activity, and rotation dynamics. To uncover the high-dimensional neural dynamical system, we further proposed a geometric framework to quantify and visualize population coding and sensory integration in a temporally defined manner. We employed dynamic epoch-wise principal component analysis (PCA) to define multiple task-specific subspaces and task-related axes, and computed the angles between task-related axes and these subspaces. In low-dimensional neural representations, the trained RNN first encoded the context cues in a cue-specific subspace, and then maintained the cue information with a stable low-activity state persisting during the delay epoch, and further formed line attractors for sensor integration through low-dimensional neural trajectories to guide decision-making. We demonstrated via intensive computer simulations that the geometric manifolds encoding the context information were robust to varying degrees of weight perturbation in both space and time. Overall, our analysis framework provides clear geometric interpretations and quantification of information coding, maintenance, and integration, yielding new insight into the computational mechanisms of context-dependent computation.

Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.

Propagation of activity in spatially structured neuronal networks has been observed in awake, anesthetized, and sleeping brains. How these wave patterns emerge and organize across brain structures, and how network connectivity affects spatiotemporal neural activity remains unclear. Here, we develop a computational model of a two-dimensional thalamocortical network, which gives rise to emergent traveling waves similar to those observed experimentally. We illustrate how spontaneous and evoked oscillatory activity in space and time emerge using a closed-loop thalamocortical architecture, sustaining smooth waves in the cortex and staggered waves in the thalamus. We further show that intracortical and thalamocortical network connectivity, cortical excitation/inhibition balance, and thalamocortical or corticothalamic delay can independently or jointly change the spatiotemporal patterns (radial, planar and rotating waves) and characteristics (speed, direction, and frequency) of cortical and thalamic traveling waves. Computer simulations predict that increased thalamic inhibition induces slower cortical frequencies and that enhanced cortical excitation increases traveling wave speed and frequency. Overall, our results provide insight into the genesis and sustainability of thalamocortical spatiotemporal patterns, showing how simple synaptic alterations cause varied spontaneous and evoked wave patterns. Our model and simulations highlight the need for spatially spread neural recordings to uncover critical circuit mechanisms for brain functions.

In this study, an infection screening system was developed to detect patients suffering from infectious diseases. In addition, the system was also designed to deal with the variability in age and gender, which would affect the accuracy of the detection. Furthermore, to enable a low-cost, non-contact and embedded system, multiple vital signs from a medical radar were measured and all algorithms were implemented on a Field Programmable Gate Array, named PYNQ-Z1.

Chronic pain alters cortical and subcortical plasticity, causing enhanced sensory and affective responses to peripheral nociceptive inputs. Previous studies have shown that ketamine had the potential to inhibit abnormally amplified affective responses of single neurons by suppressing hyperactivity in the anterior cingulate cortex (ACC). However, the mechanism of this enduring effect has yet to be understood at the network level. In this study, we recorded local field potentials from the ACC of freely moving rats. Animals were injected with complete Freund's adjuvant (CFA) to induce persistent inflammatory pain. Mechanical stimulations were administered to the hind paw before and after CFA administration. We found a significant increase in the high-gamma band (60-100 Hz) power in response to evoked pain after CFA treatment. Ketamine, however, reduced the high-gamma band power in response to evoked pain in CFA-treated rats. In addition, ketamine had a sustained effect on the high-gamma band power lasting up to five days after a single dose administration. These results demonstrate that ketamine has the potential to alter maladaptive neural responses in the ACC induced by chronic pain.

Exploring the neural circuits of the extinction of conditioned fear is critical to advance our understanding of fear- and anxiety-related disorders. The field has focused on examining the role of various regions of the medial prefrontal cortex, insular cortex, hippocampus, and amygdala in conditioned fear and its extinction. The contribution of this 'fear network' to the conscious awareness of fear has recently been questioned. And as such, there is a need to examine higher/multiple cortical systems that might contribute to the conscious feeling of fear and anxiety. Herein, we studied functional connectivity patterns across the entire brain to examine the contribution of multiple networks to the acquisition of fear extinction learning and its retrieval. We conducted trial-by-trial analyses on data from 137 healthy participants who underwent a two-day fear conditioning and extinction paradigm in a functional magnetic resonance imaging (fMRI) scanner. We found that functional connectivity across a broad range of brain regions, many of which are part of the default mode, frontoparietal, and ventral attention networks, increased from early to late extinction learning only to a conditioned cue. The increased connectivity during extinction learning predicted the magnitude of extinction memory tested 24 h later. Together, these findings provide evidence supporting recent studies implicating distributed brain regions in learning, consolidation and expression of fear extinction memory in the human brain.

As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.

The Kelch repeat and BTB domain containing 7 (KBTBD7) was first cloned in 2010. Its function as a transcriptional activator and a substrate adaptor during the ubiquitination process was soon found. KBTBD7 was shown to be involved in excessive inflammation after myocardial infarction, brain development, and neurofibromin stability. However, studies on the role of KBTBD7 in solid tumors, especially lung cancer, are still lacking. Therefore, in this study, we investigate the role of KBTBD7 in non-small cell lung cancer (NSCLC). Immunohistochemical staining of 104 paired NSCLC and peritumoral normal specimens indicated that KBTBD7 was highly expressed in NSCLC tissues and positively correlated with the histological type, P-TNM stage, lymph node metastasis, and tumor size. KBTBD7 was also well-expressed in NSCLC cell lines, and downregulation of KBTBD7 resulted in inhibition of NSCLC cell proliferation and invasion. Further investigation showed that KBTBD7 enhanced ubiquitin-dependent degradation of PTEN, thus activating EGFR/PI3K/AKT signaling and promoting NSCLC cell proliferation and invasion by regulating CCNE1, CDK4, P27, ZEB-1, Claudin-1, ROCK1, MMP-9, and E-cadherin protein levels. Our results indicate that KBTBD7 may be a potential therapeutic target for the treatment of NSCLC.

Spatially modulated grid cells have been recently found in the rat secondary visual cortex (V2) during active navigation. However, the computational mechanism and functional significance of V2 grid cells remain unknown. To address the knowledge gap, we train a biologically inspired excitatory-inhibitory recurrent neural network to perform a two-dimensional spatial navigation task with multisensory input. We find grid-like responses in both excitatory and inhibitory RNN units, which are robust with respect to spatial cues, dimensionality of visual input, and activation function. Population responses reveal a low-dimensional, torus-like manifold and attractor. We find a link between functional grid clusters with similar receptive fields and structured excitatory-to-excitatory connections. Additionally, multistable torus-like attractors emerged with increasing sparsity in inter- and intra-subnetwork connectivity. Finally, irregular grid patterns are found in recurrent neural network (RNN) units during a visual sequence recognition task. Together, our results suggest common computational mechanisms of V2 grid cells for spatial and non-spatial tasks.

Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain-machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top-down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.

Long noncoding RNAs (lncRNAs) are critical players during cancer progression. Nevertheless, the effect of most lncRNAs in lung cancer (LC) remains unclear. We aimed to explore the role of LINC01342 in LC development through the microRNA-508-5p (miR-508-5p)/cysteine-rich secretory protein 3 (CRISP3) axis. LINC01342, miR-508-5p, and CRISP3 expression in clinical samples and cell lines were determined, and their correlations in LC were analyzed. The prognostic role of LINC01342 in LC patients was evaluated. LC cells were screened and, respectively, transfected to alter the expression of LINC01342, miR-508-5p, and CRISP3. Then, proliferation, migration, invasion, and apoptosis of transfected LC cells were determined, and the in vivo tumor growth was observed as well. Binding relationships between LINC01342 and miR-508-5p, and between miR-508-5p and CRISP3 were identified. LINC01342 and CRISP3 were upregulated and miR-508-5p was downregulated in LC tissues and cells. High LINC01342 expression indicated a poor prognosis of LC patients. The LINC01342/CRISP3 silencing or miR-508-5p elevation inhibited proliferation, migration, and invasion of LC cells and promoted LC cell apoptosis, and also suppressed the in vivo tumor growth. LINC01342 bound to miR-508-5p and miR-508-5p targeted CRISP3. LINC01342 plays a prognostic role in LC and LINC01342 silencing upregulates miR-508-5p to inhibit the progression of LC by reducing CRISP3.

The prefrontal cortex (PFC) regulates a wide range of sensory experiences. Chronic pain is known to impair normal neural response, leading to enhanced aversion. However, it remains unknown how nociceptive responses in the cortex are processed at the population level and whether such processes are disrupted by chronic pain. Using in vivo endoscopic calcium imaging, we identify increased population activity in response to noxious stimuli and stable patterns of functional connectivity among neurons in the prelimbic (PL) PFC from freely behaving rats. Inflammatory pain disrupts functional connectivity of PFC neurons and reduces the overall nociceptive response. Interestingly, ketamine, a well-known neuromodulator, restores the functional connectivity among PL-PFC neurons in the inflammatory pain model to produce anti-aversive effects. These results suggest a dynamic resource allocation mechanism in the prefrontal representations of pain and indicate that population activity in the PFC critically regulates pain and serves as an important therapeutic target.

Background: In the last two decades, infrared thermography (IRT) has been applied in quarantine stations for the screening of patients with suspected infectious disease. However, the fever-based screening procedure employing IRT suffers from low sensitivity, because monitoring body temperature alone is insufficient for detecting infected patients. To overcome the drawbacks of fever-based screening, this study aims to develop and evaluate a multiple vital sign (i.e., body temperature, heart rate and respiration rate) measurement system using RGB-thermal image sensors. Methods: The RGB camera measures blood volume pulse (BVP) through variations in the light absorption from human facial areas. IRT is used to estimate the respiration rate by measuring the change in temperature near the nostrils or mouth accompanying respiration. To enable a stable and reliable system, the following image and signal processing methods were proposed and implemented: (1) an RGB-thermal image fusion approach to achieve highly reliable facial region-of-interest tracking, (2) a heart rate estimation method including a tapered window for reducing noise caused by the face tracker, reconstruction of a BVP signal with three RGB channels to optimize a linear function, thereby improving the signal-to-noise ratio and multiple signal classification (MUSIC) algorithm for estimating the pseudo-spectrum from limited time-domain BVP signals within 15 s and (3) a respiration rate estimation method implementing nasal or oral breathing signal selection based on signal quality index for stable measurement and MUSIC algorithm for rapid measurement. We tested the system on 22 healthy subjects and 28 patients with seasonal influenza, using the support vector machine (SVM) classification method. Results: The body temperature, heart rate and respiration rate measured in a non-contact manner were highly similarity to those measured via contact-type reference devices (i.e., thermometer, ECG and respiration belt), with Pearson correlation coefficients of 0.71, 0.87 and 0.87, respectively. Moreover, the optimized SVM model with three vital signs yielded sensitivity and specificity values of 85.7% and 90.1%, respectively. Conclusion: For contactless vital sign measurement, the system achieved a performance similar to that of the reference devices. The multiple vital sign-based screening achieved higher sensitivity than fever-based screening. Thus, this system represents a promising alternative for further quarantine procedures to prevent the spread of infectious diseases.

High-speed widefield fluorescence microscopy has the potential to capture biological processes with exceptional spatiotemporal resolution. However, conventional cameras suffer from low signal-to-noise ratio (SNR) at high frame rates, limiting their ability to detect faint fluorescent events. Here we introduce an image sensor where each pixel has individually programmable sampling speed and phase, so that pixels can be arranged to simultaneously sample at high speed with a high SNR. In high-speed voltage imaging experiments, our image sensor significantly increases the output SNR compared to a low-noise scientific CMOS camera (~2-3 folds). This SNR gain enables the detection of weak neuronal action potentials and subthreshold activities missed by the standard scientific CMOS cameras. Our proposed camera with flexible pixel exposure configurations offers versatile sampling strategies to improve signal quality in various experimental conditions.