NRSF regulates age-dependently cognitive ability and its conditional knockout in APP/PS1 mice moderately alters AD-like pathology.

NRSF/REST (neuron-restrictive silencer element, also known as repressor element 1-silencing transcription factor), plays a key role in neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST relates to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease (AD)-related memory deficits remain unclear. Here, we show that conditional NRSF/REST knockout either in the dorsal telencephalon or specially in neurons induced an age-dependently diminished retrieval performance in spatial or fear conditioning memory tasks and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. The NRSF/REST deficient mice were also characterized by an increase of activated glial cells, complement C3 protein and the transcription factor C/EBPß in the cortex and hippocampus. Reduction of NRSF/REST by conditional depletion upregulated the activation of astrocytes in APP/PS1 mice, and increased the C3-positive glial cells, but did not alter the Aß loads and memory retrieval performances of 6- and 12-month-old APP/PS1 mice. Simultaneously, overexpression of NRSF/REST improved cognitive abilities of aged wild type, but not in AD mice. These findings demonstrated that NRSF/REST is essential for the preservation of memory performance and activity-dependent synaptic plasticity during aging and takes potential roles in the onset of age-related memory impairments. However, while altering the glial activation, NRSF/REST deficiency does not interfere with the Aß deposits and the electrophysiological and cognitive AD-like pathologies.

EEGManyPipelines: A Large-scale, Grassroots Multi-analyst Study of Electroencephalography Analysis Practices in the Wild.

The ongoing reproducibility crisis in psychology and cognitive neuroscience has sparked increasing calls to re-evaluate and reshape scientific culture and practices. Heeding those calls, we have recently launched the EEGManyPipelines project as a means to assess the robustness of EEG research in naturalistic conditions and experiment with an alternative model of conducting scientific research. One hundred sixty-eight analyst teams, encompassing 396 individual researchers from 37 countries, independently analyzed the same unpublished, representative EEG data set to test the same set of predefined hypotheses and then provided their analysis pipelines and reported outcomes. Here, we lay out how large-scale scientific projects can be set up in a grassroots, community-driven manner without a central organizing laboratory. We explain our recruitment strategy, our guidance for analysts, the eventual outputs of this project, and how it might have a lasting impact on the field.

Preexposure to one social threat alters responses to another social threat: Behavioral and electrophysiological evidence.

A recent Cyberball study has indicated that the experience of loss of control can affect how people process subsequent social exclusion. This "preexposure effect" supports the idea of a common cognitive system involved in the processing of different types of social threats. To test the validity of this assumption in the current study, we reversed the sequence of the preexposure setup. We measured the effects of social exclusion on the subsequent processing of loss of control utilizing event-related brain potentials (ERPs) and self-reports. In the control group (CG, n = 26), the transition to loss of control elicited significant increases in both the P3 amplitude and the self-reported negative mood. Replicating the results of the previous preexposure study, these effects were significantly reduced by the preexposure to an independent social threat (here: social exclusion). In contrast to previous findings, these effects were not modulated by the discontinuation (EG1disc, n = 25) or continuation (EG2cont, n = 24) of the preexposure threat. Given that the P3 effect is related to the violation of subjective expectations, these results support the notion that preexposure to a specific social threat has widespread effects on the individuals' expectancy of upcoming social participation and control.

Generation of true quantum random numbers with on-demand probability distributions via single-photon quantum walks.

Random numbers are at the heart of diverse fields, ranging from simulations of stochastic processes to classical and quantum cryptography. The requirement for true randomness in these applications has motivated various proposals for generating random numbers based on the inherent randomness of quantum systems. The generation of true random numbers with arbitrarily defined probability distributions is highly desirable for applications, but it is very challenging. Here we show that single-photon quantum walks can generate multi-bit random numbers with on-demand probability distributions, when the required "coin" parameters are found with the gradient descent (GD) algorithm. Our theoretical and experimental results exhibit high fidelity for various selected distributions. This GD-enhanced single-photon system provides a convenient way for building flexible and reliable quantum random number generators. Multi-bit random numbers are a necessary resource for high-dimensional quantum key distribution.

NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.

Parkinson's disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1ß, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3ß and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.

Progressive alterations in electrophysiological and epileptic network properties during the development of temporal lobe epilepsy in rats.

OBJECTIVE: Refractory temporal lobe epilepsy (TLE) with recurring seizures causing continuing pathological changes in neural reorganization. There is an incomplete understanding of how spatiotemporal electrophysiological characteristics changes during the development of TLE. Long-term multi-site epilepsy patients' data is hard to obtain. Thus, our study relied on animal models to reveal the changes in electrophysiological and epileptic network characteristics systematically. METHODS: Long-term local field potentials (LFPs) were recorded over a period of 1 to 4 months from 6 pilocarpine-treated TLE rats. We compared variations of seizure onset zone (SOZ), seizure onset pattern (SOP), the latency of seizure onsets, and functional connectivity network from 10-channel LFPs between the early and late stages. Moreover, three machine learning classifiers trained by early-stage data were used to test seizure detection performance in the late stage. RESULTS: Compared to the early stage, the earliest seizure onset was more frequently detected in hippocampus areas in the late stage. The latency of seizure onsets between electrodes became shorter. Low-voltage fast activity (LVFA) was the most common SOP and the proportion of it increased in the late stage. Different brain states were observed during seizures using Granger causality (GC). Moreover, seizure detection classifiers trained by early-stage data were less accurate when tested in late-stage data. SIGNIFICANCE: Neuromodulation especially closed-loop deep brain stimulation (DBS) is effective in the treatment of refractory TLE. Although the frequency or amplitude of the stimulation is generally adjusted in existing closed-loop DBS devices in clinical usage, the adjustment rarely considers the pathological progression of chronic TLE. This suggests that an important factor affecting the therapeutic effect of neuromodulation may have been overlooked. The present study reveals time-varying electrophysiological and epileptic network properties in chronic TLE rats and indicates that classifiers of seizure detection and neuromodulation parameters might be designed to adapt to the current state dynamically with the progression of epilepsy.

Efficacy of different strategies of responsive neurostimulation on seizure control and their association with acute neurophysiological effects in rats.

Responsive neurostimulation (RNS) has shown promising but limited efficacy in the treatment of drug-resistant epilepsy. The clinical utility of RNS is hindered by the incomplete understanding of the mechanism behind its therapeutic effects. Thus, assessing the acute effects of responsive stimulation (AERS) based on intracranial EEG recordings in the temporal lobe epilepsy rat model may provide a better understanding of the potential therapeutic mechanisms underlying the antiepileptic effect of RNS. Furthermore, clarifying the correlation between AERS and seizure severity may help guide the optimization of RNS parameter settings. In this study, RNS with high (130 Hz) and low frequencies (5 Hz) was applied to the subiculum (SUB) and CA1. To quantify the changes induced by RNS, we calculated the AERS during synchronization by Granger causality and analyzed the band power ratio in the classic power band after different stimulations were delivered in the interictal and seizure onset periods, respectively. This demonstrates that only targets combined with an appropriate stimulation frequency could be efficient for seizure control. High-frequency stimulation of CA1 significantly shortened the ongoing seizure duration, which may be causally related to increased synchronization after stimulation. Both high-frequency stimulation of the CA1 and low-frequency stimulation delivered to the SUB reduced seizure frequency, and the reduced seizure risk may correlate with the change in power ratio near the theta band. It indicated that different stimulations may control seizures in diverse manners, perhaps with disparate mechanisms. More focus should be placed on understanding the correlation between seizure severity and synchronization and rhythm around theta bands to simplify the process of parameter optimization.

The Neural Basis of Semantic Prediction in Sentence Comprehension.

Although prediction plays an important role in language comprehension, its precise neural basis remains unclear. This fMRI study investigated whether and how semantic-category-specific and common cerebral areas are recruited in predictive semantic processing during sentence comprehension. We manipulated the semantic constraint of sentence contexts, upon which a tool-related, a building-related, or no specific category of noun is highly predictable. This noun-predictability effect was measured not only over the target nouns but also over their preceding transitive verbs. Both before and after the appearance of target nouns, left anterior supramarginal gyrus was specifically activated for tool-related nouns and left parahippocampal place area was activated specifically for building-related nouns. The semantic-category common areas included a subset of left inferior frontal gyrus during the anticipation of incoming target nouns (activity enhancement for high predictability) and included a wide spread of areas (bilateral inferior frontal gyrus, left superior/middle temporal gyrus, left medial pFC, and left TPJ) during the integration of actually perceived nouns (activity reduction for high predictability). These results indicated that the human brain recruits fine divisions of cortical areas to distinguish different semantic categories of predicted words, and anticipatory semantic processing relies, at least partially, on top-down prediction conducted in higher-level cortical areas.

Music-induced emotions influence intertemporal decision making.

People tend to choose smaller, immediate rewards over larger, delayed rewards. This phenomenon is thought to be associated with emotional engagement. However, few studies have demonstrated the real-time impact of incidental emotions on intertemporal choices. This research investigated the effects of music-induced incidental emotions on intertemporal choices, during which happy or sad music was played simultaneously. We found that music-induced happiness made participants prefer smaller-but-sooner rewards (SS), whereas music-induced sadness made participants prefer larger-but-later rewards (LL). Time perception partially mediated this effect: the greater the perceived temporal difference, the more likely they were to prefer SS. Tempo and mode were then manipulated to disentangle the effects of arousal and mood on intertemporal choices. Only tempo-induced arousal, but not mode-induced mood, affected intertemporal choices. These results suggest the role of arousal in intertemporal decision making and provide evidence in support of equate-to-differentiate theory with regard to the non-compensatory mechanism in intertemporal choices.

Contextual prediction modulates musical tension: Evidence from behavioral and neural responses.

Tension is a bridge between music structure and emotion. It is known that tension is affected by prediction in music listening as music unfolds. Combining behavioral and neural responses, the current research investigated how musical predictions influence tension in the process of prediction build-up based on musical context (anticipatory stage) and its integration with upcoming stimuli (integration stage). The results showed that, at the anticipatory stage, compared with high-prediction conditions, in low-prediction conditions tension curve changed faster and unstable, and a larger N5 in ERP response was elicited. Furthermore, at the integration stage, compared with congruent conditions, in incongruent conditions the behavioral rating of tension were higher regardless of the predictability of the final chord; a right negativity and P600 were elicited, and the amplitude of P600 was modulated by the predictability of the final chord. These results indicated that the effect of prediction on tension was modulated by contextual predictability. The findings provide a more comprehensive view on how musical prediction affects musical tension.

Prevalence and predictors of posttraumatic stress disorder, depression and anxiety among hospitalized patients with coronavirus disease 2019 in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has affected more than 5 million people around the world and killed more than 300,000 people; thus, it has become a global public health emergency. Our objective was to investigate the mental health of hospitalized patients diagnosed with COVID-19. METHODS: The PTSD checklist for DSM-5 (PCL-5), Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7), Trauma Exposure Scale, abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC-10), Perceived Social Support Scale (PSSS) and Demographic Questionnaire were used to examine posttraumatic stress disorder (PTSD), depression, anxiety, trauma exposure, resilience and perceived social support among 898 patients who were hospitalized after being diagnosed with COVID-19 in China. The data were analyzed with t tests, one-way ANOVA and multivariable logistic regression analysis. RESULTS: The results showed that the prevalence of PTSD, depression and anxiety was 13.2, 21.0 and 16.4%, respectively. Hospitalized patients who were more impacted by negative news reports, had greater exposure to traumatic experiences, and had lower levels of perceived social support reported higher PTSD, depression and anxiety. CONCLUSIONS: Effective professional mental health services should be designed to support the psychological wellbeing of hospitalized patients, especially those who have severe disease, are strongly affected by negative news and have high levels of exposure to trauma.

Rhubarb and Astragalus Capsule Attenuates Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction by Alleviating Apoptosis through Regulating Transforming Growth Factor beta1 (TGF-ß1)/p38 Mitogen-Activated Protein Kinases (p38 MAPK) Pathway.

BACKGROUND Rhubarb and astragalus capsule (RAC) has been used in the clinical treatment of chronic kidney disease for decades. However, the mechanism of RAC has not been fully elucidated. This study aimed to investigate the protective effect and mechanisms of RAC on unilateral ureteral obstruction (UUO)-induced renal interstitial fibrosis. MATERIAL AND METHODS The main components of RAC are detected by high-performance liquid phase (HPLC). A rat model of UUO was established, and a subset of rats underwent treatment with RAC. Renal function and renal pathology were examined at 14 days and 21 days after the UUO operation. Renal cell apoptosis was detected by TUNEL staining. The levels of Bcl-2 and Bax in the kidney were examined by western blotting, and the levels of collagen I, alpha-SMA, transforming growth factor (TGF)-ß1, and p38 MAPK in the kidneys were detected by immunohistochemistry. RESULTS High-performance liquid phase chromatography showed that RAC contained 1.12 mg/g aloe-emodin, 2.25 mg/g rhein, 1.75 mg/g emodin, and 4.50 mg/g chrysophanol. Administration of RAC significantly decreased the levels of urinary N-acetyl-ß-D-glucosaminidase (NAG), serum blood urea nitrogen (BUN), and creatinine (Scr) and also reduced renal tissue damages and interstitial fibrosis induced by UUO in rats. Moreover, the increased levels of collagen I, alpha-SMA, TGF-ß1, p38 MAPK, and the Bax/Bcl-2 ratio, as well as cell apoptosis in the kidney, were induced by UUO, and were all found deceased by RAC treatment. CONCLUSIONS RAC can improve the renal interstitial fibrosis induced by UUO, and the mechanism may be related to inhibition of renal tubular cell apoptosis via TGF-ß1/p38 MAPK pathway.

Static Ultrasound Guidance VS. Anatomical Landmarks for Subclavian Vein Puncture in the Intensive Care Unit: A Pilot Randomized Controlled Study.

BACKGROUND: Subclavian vein puncture is commonly used in the intensive care unit (ICU) but is associated with complications. OBJECTIVE: Our aim was to compare the efficacy and safety of static ultrasound-guided subclavian vein puncture with traditional anatomical landmark-guided subclavian vein puncture in critically ill patients in the ICU. METHODS: This pilot randomized controlled trial enrolled patients admitted to the ICU and requiring subclavian vein puncture between November 2017 and September 2018. The patients were randomized to ultrasound-guided puncture or anatomical landmark-guided puncture. The primary outcome measure was the puncture success rate. The secondary outcome measures included the number of punctures, rate of success at the first attempt, puncture time (i.e., procedure duration) and incidence of complications. RESULTS: A total of 194 patients were included in the analyses. Compared with the anatomical landmarks group, the ultrasound group had a higher puncture success rate (91.7% vs. 77.6%; p = 0.007), lower rate of complications (7.3% vs. 20.4%; p = 0.008), and lower incidence of mispuncture of an artery (2.1% vs. 14.3%; p = 0.002). There were no significant differences in the number of punctures and puncture time between the two groups (both, p > 0.05). CONCLUSIONS: Static ultrasound-guided subclavian vein puncture is superior to the traditional landmark-guided approach for critically ill patients in the ICU. It is suggested that static ultrasound-guided puncture techniques should be considered for subclavian vein puncture in the ICU. TRIAL REGISTRATION: ChiCTR1900024051.

Uncovering cortical activations of discourse comprehension and their overlaps with common large-scale neural networks.

We conducted a meta-analysis of 78 task-based functional magnetic resonance imaging (fMRI) studies (1976 total participants) to reveal underlying brain activations and their overlap with large-scale neural networks in the brain during general discourse comprehension and its sub-processes. We found that discourse comprehension involved a neural system consisting of widely distributed brain regions that comprised not only the bilateral perisylvian language zones, but also regions in the superior and medial frontal cortex and the medial temporal lobe. Moreover, this neural system can be categorized into several sub-systems representing various sub-processes of discourse comprehension, with the left inferior frontal gyrus and middle temporal gyrus serving as core regions across all sub-processes. At a large-scale network level, we found that discourse comprehension relied most heavily on the default network, particularly on its dorsal medial subsystem. The pattern associated with large-scale network cooperation varied according to the respective sub-processes required. Our results reveal the functional dissociation within the discourse comprehension neural system and highlight the flexible involvements of large-scale networks.

Concurrent emotional response and semantic unification: An event-related potential study.

Using event-related potentials, in this study we examined how implied emotion is derived from sentences. In the same sentential context, different emotionally neutral words rendered the whole sentence emotionally neutral and semantically congruent, emotionally negative and semantically congruent, or emotionally neutral and semantically incongruent. Relative to the words in the neutral-congruent condition, the words in the neutral-incongruent condition elicited a larger N400, indicating increased semantic processing, whereas the words in the negative-congruent condition elicited a long-lasting positivity between 300 and 1,000 ms, indicating an emotional response. The overlapping time windows of semantic processing and the emotional response suggest that the construction of emotional meaning operates concurrently with semantic unification. The results indicate that the implied emotional processing of sentences may be a result of unification operations but does not necessarily involve causal appraisal of a sentence's mental representation.

The pretreatment of chronic restraint stress exerts little impact on the progression of heart failure in mice.

Stress is a potent risk factor for depression. Chronic stress can exacerbate and induce symptoms of depression. Clinical studies suggested that depressive patients are more likely to develop coronary artery diseases. However, the causal relationship between depression and heart failure progression remains unclear. In this study, we aimed to explore the relevance between stress and heart failure (HF) in a mouse model subjected to chronic restraint stress and left anterior descending coronary artery (LAD) ligation. Mice were restrained for 3 h daily for 21 days and the processes were repeated once 3 months later. After the repeated chronic restraint stress, mice showed dramatically increased immobility time in the forced swim test, indicating a state of despair. Restrained and control mice were further subjected to LAD ligation surgery. Echocardiography was conducted 1 week, 2 weeks, and 1 month afterward. LAD-operated mice showed a significant decrease in the values of left ventricular ejection fraction (LVEF), and there was no difference in the LVEF values between the restrained and control mice. Relevant gene expression, neurotransmitter system, glial activation, and morphology of the heart-brain axis were comprehensively evaluated. We found no overall differences between the restrained and control mice with HF. Our results revealed that the repeated chronic restraint stress may have little effects on the progression of heart failure.

A 3D Coverage Algorithm Based on Complex Surfaces for UAVs in Wireless Multimedia Sensor Networks.

Following the development of wireless multimedia sensor networks (WMSN), the coverage of the sensors in the network constitutes one of the key technologies that have a significant influence on the monitoring ability, quality of service, and network lifetime. The application environment of WMSN is always a complex surface, such as a hilly surface, that would likely cause monitoring shadowing problems. In this study, a new coverage-enhancing algorithm is presented to achieve an optimal coverage ratio of WMSN based on three-dimensional (3D) complex surfaces. By aiming at the complex surface, the use of a 3D sensing model, including a sensor monitoring model and a surface map calculation algorithm, is proposed to calculate the WMSN coverage information in an accurate manner. The coverage base map allowed the efficient estimation of the degree of monitoring occlusion efficiently and improved the system's accuracy. To meet the requests of complex 3D surface monitoring tasks for multiple sensors, we propose a modified cuckoo search algorithm that considers the features of the WMSN coverage problem and combines the survival of the fittest, dynamic discovery probability, and the self-adaptation strategy of rotation. The evaluation outcomes demonstrate that the proposed algorithm can describe the 3D covering field but also improve both the coverage quality and efficiency of the WMSN on a complex surface.

Temporal neural mechanisms underlying conscious access to different levels of facial stimulus contents.

An important issue facing the empirical study of consciousness concerns how the contents of incoming stimuli gain access to conscious processing. According to classic theories, facial stimuli are processed in a hierarchical manner. However, it remains unclear how the brain determines which level of stimulus content is consciously accessible when facing an incoming facial stimulus. Accordingly, with a magnetoencephalography technique, this study aims to investigate the temporal dynamics of the neural mechanism mediating which level of stimulus content is consciously accessible. Participants were instructed to view masked target faces at threshold so that, according to behavioral responses, their perceptual awareness alternated from consciously accessing facial identity in some trials to being able to consciously access facial configuration features but not facial identity in other trials. Conscious access at these two levels of facial contents were associated with a series of differential neural events. Before target presentation, different patterns of phase angle adjustment were observed between the two types of conscious access. This effect was followed by stronger phase clustering for awareness of facial identity immediately during stimulus presentation. After target onset, conscious access to facial identity, as opposed to facial configural features, was able to elicit more robust late positivity. In conclusion, we suggest that the stages of neural events, ranging from prestimulus to stimulus-related activities, may operate in combination to determine which level of stimulus contents is consciously accessed. Conscious access may thus be better construed as comprising various forms that depend on the level of stimulus contents accessed. NEW & NOTEWORTHY The present study investigates how the brain determines which level of stimulus contents is consciously accessible when facing an incoming facial stimulus. Using magnetoencephalography, we show that prestimulus activities together with stimulus-related activities may operate in combination to determine conscious face detection or identification. This finding is distinct from the previous notion that conscious face detection precedes identification and provides novel insights into the temporal dynamics of different levels of conscious face perception.

The dynamic influence of emotional words on sentence comprehension: An ERP study.

In the present study, we explored the influence of emotional words on the semantic integration of their following neutral nouns during sentence comprehension. We manipulated the emotionality of verbs and the semantic congruity of their following (neutral) object nouns in sentences. Event-related potentials were recorded to the verbs, which were either negative or neutral, and to the object nouns, which were either semantically congruent or incongruent relative to the preceding contexts. We found an N400 and a P600 effect in response to the semantic congruity of the nouns when they followed the neutral verbs. However, the P600 (but not the N400) semantic congruity effect may have been attenuated when the nouns followed the negative verbs. Meanwhile, the negative verbs elicited a larger P2 and N400 than did the neutral verbs. The results indicate that the attention captured by emotional words impaired reanalysis of the following incongruent information, demonstrating a dynamic influence of emotional words on the semantic processing of following information during sentence comprehension.

The processing difference between person names and common nouns in sentence contexts: an ERP study.

Person names and common nouns differ in how they are stored in the mental lexicon. Using event-related potentials, this study compared the integration of names and nouns into sentence contexts. Both person names and common nouns were highly related in meaning and either congruent or incongruent within the previous contexts. Name incongruence elicited an N400 effect, suggesting that people were able to rapidly retrieve the semantic meaning of names from long-term memory even when this process was mediated by person identification. Conversely, participants showed a "good enough" processing of the nouns due to their low specificity level and, thus, rich semantic associations, leading to a P600 effect. These distinctive ERP effects provide clear evidence for the distinctive semantic representations of these word categories by showing that the activation of a name's meaning is mediated by a single connection between identity-specific information and person identity, whereas multiple connections exist between nouns and their meanings.