Excitatory-inhibitory mismatch shapes node recruitment in an epileptic network.

OBJECTIVE: Focal epilepsy is thought to be a network disease, in which epileptiform activity can spread noncontiguously through the brain via highly interconnected nodes, or hubs, within existing networks. Animal models confirming this hypothesis are scarce, and our understanding of how distant nodes are recruited is also lacking. Whether interictal spikes (IISs) also create and reverberate through a network is not well understood. METHODS: We injected bicuculline into the S1 barrel cortex and employed multisite local field potential and Thy-1 and parvalbumin (PV) cell mesoscopic calcium imaging during IISs to monitor excitatory and inhibitory cells in two monosynaptically connected nodes and one disynaptically connected node: ipsilateral secondary motor area (iM2), contralateral S1 (cS1), and contralateral secondary motor area (cM2). Node participation was analyzed with spike-triggered coactivity maps. Experiments were repeated with 4-aminopyridine as an epileptic agent. RESULTS: We found that each IIS reverberated throughout the network, differentially recruiting both excitatory and inhibitory cells in all connected nodes. The strongest response was found in iM2. Paradoxically, node cM2, which was connected disynaptically to the focus, was recruited more intensely than node cS1, which was connected monosynaptically. The explanation for this effect could be found in node-specific excitatory/inhibitory (E/I) balance, as cS1 demonstrated greater PV inhibitory cell activation compared with cM2, where Thy-1 excitatory cells were more heavily recruited. SIGNIFICANCE: Our data show that IISs spread noncontiguously by exploiting fiber pathways that connect nodes in a distributed network and that E/I balance plays a critical role in node recruitment. This multinodal IIS network model can be used to investigate cell-specific dynamics in the spatial propagation of epileptiform activity.

Seizures initiate in zones of relative hyperexcitation in a zebrafish epilepsy model.

Seizures are thought to arise from an imbalance of excitatory and inhibitory neuronal activity. While most classical studies suggest excessive excitatory neural activity plays a generative role, some recent findings challenge this view and instead argue that excessive activity in inhibitory neurons initiates seizures. We investigated this question of imbalance in a zebrafish seizure model with two-photon imaging of excitatory and inhibitory neuronal activity throughout the brain using a nuclear-localized calcium sensor. We found that seizures consistently initiated in circumscribed zones of the midbrain before propagating to other brain regions. Excitatory neurons were both more prevalent and more likely to be recruited than inhibitory neurons in initiation as compared with propagation zones. These findings support a mechanistic picture whereby seizures initiate in a region of hyperexcitation, then propagate more broadly once inhibitory restraint in the surround is overcome.

A Novel ST-YOLO Network for Steel-Surface-Defect Detection.

Recent progress has been made in defect detection using methods based on deep learning, but there are still formidable obstacles. Defect images have rich semantic levels and diverse morphological features, and the model is dynamically changing due to ongoing learning. In response to these issues, this article proposes a shunt feature fusion model (ST-YOLO) for steel-defect detection, which uses a split feature network structure and a self-correcting transmission allocation method for training. The network structure is designed to specialize the process of classification and localization tasks for different computing needs. By using the self-correction criteria of adaptive sampling and dynamic label allocation, more sufficiently high-quality samples are utilized to adjust data distribution and optimize the training process. Our model achieved better performance on the NEU-DET datasets and the GC10-DET datasets and was validated to exhibit excellent performance.

The diagnostic value of soluble TIM-3 in oral squamous cell carcinoma.

Objective: To evaluate the soluble TIM-3 (sTIM-3) expression level in oral squamous cell carcinoma (OSCC) and determine its clinical diagnostic potential. Methods: The sTIM-3 and squamous cell carcinoma antigen (SCCAg) levels of 199 OSCC patients and 107 healthy individuals were assessed using an enzyme-linked immunosorbent assay and their individual and combined efficiency rates were compared. Results: The results showed higher sTIM-3 and SCCAg levels in the OSCC patients and better diagnostic potential for a combination of these markers than for their individual assessments, as well as positive correlation of sTIM-3 levels with clinicopathological factors. Conclusion: sTIM-3 is a potential novel and readily accessible OSCC biomarker, which in combination with SCCAg expression level might better diagnose OSCC patients.

Lay abstract Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. It affects the patients' swallowing, speech, appearance, social interactions and other aspects. Soluble TIM-3 (sTIM-3) is a negative regulatory molecule. Serum levels of squamous cell carcinoma antigen are closely related to the growth of OSCC tumors. Herein, the serum levels of sTIM-3 in OSCC patients were examined. This study demonstrated that the combined assessment of sTIM-3 and squamous cell carcinoma antigen expression levels might better distinguish OSCC patients from healthy individuals.

Burst suppression uncovers rapid widespread alterations in network excitability caused by an acute seizure focus.

Burst suppression is an electroencephalogram pattern of globally symmetric alternating high amplitude activity and isoelectricity that can be induced by general anaesthetics. There is scattered evidence that burst suppression may become spatially non-uniform in the setting of underlying pathology. Here, we induced burst suppression with isoflurane in rodents and then created a neocortical acute seizure focus with injection of 4-aminopyridine (4-AP) in somatosensory cortex. Burst suppression events were recorded before and after creation of the focus using bihemispheric wide-field calcium imaging and multielectrode arrays. We find that the seizure focus elicits a rapid alteration in triggering, initiation, and propagation of burst suppression events. Compared with the non-seizing brain, bursts are triggered from the thalamus, initiate in regions uniquely outside the epileptic focus, elicit marked increases of multiunit activity and propagate towards the seizure focus. These findings support the rapid, widespread impact of focal epilepsy on the extended brain network.

In Vivo Femtosecond Laser Subsurface Cortical Microtransections Attenuate Acute Rat Focal Seizures.

Recent evidence shows that seizures propagate primarily through supragranular cortical layers. To selectively modify these circuits, we developed a new technique using tightly focused, femtosecond infrared laser pulses to make as small as ~100 µm-wide subsurface cortical incisions surrounding an epileptic focus. We use this "laser scalpel" to produce subsurface cortical incisions selectively to supragranular layers surrounding an epileptic focus in an acute rodent seizure model. Compared with sham animals, these microtransections completely blocked seizure initiation and propagation in 1/3 of all animals. In the remaining animals, seizure frequency was reduced by 2/3 and seizure propagation reduced by 1/3. In those seizures that still propagated, it was delayed and reduced in amplitude. When the recording electrode was inside the partially isolated cube and the seizure focus was on the outside, the results were even more striking. In spite of these microtransections, somatosensory responses to tail stimulation were maintained but with reduced amplitude. Our data show that just a single enclosing wall of laser cuts limited to supragranular layers led to a significant reduction in seizure initiation and propagation with preserved cortical function. Modification of this concept may be a useful treatment for human epilepsy.

Role of inhibitory control in modulating focal seizure spread.

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3-mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after both neuronal and hemodynamic onset. Glial calcium waves exhibited a stereotypical spread that terminated prior to seizure offset and propagated to an area ~60% greater than the propagation area of neural and vascular signals. Complete blockage of glial activity with fluoroacetate resulted in no change in either neuronal or hemodynamic activity. These ictal glial waves were blocked by carbenoxolone, a gap junction blocker. Our in vivo data reveal that ictal events trigger a slowly propagating, stereotypical glial calcium wave, mediated by gap junctions, that is spatially and temporally independent of neuronal and hemodynamic activities. We introduce a novel ictally triggered propagating glial calcium wave calling into question the criticality of glial calcium wave in both ictal onset and neurovascular coupling.

ERα Mediates Estrogen-Induced Expression of the Breast Cancer Metastasis Suppressor Gene BRMS1.

Recently, estrogen has been reported as putatively inhibiting cancer cell invasion and motility. This information is in direct contrast to the paradigm of estrogen as a tumor promoter. However, data suggests that the effects of estrogen are modulated by the receptor isoform with which it interacts. In order to gain a clearer understanding of the role of estrogen in potentially suppressing breast cancer metastasis, we investigated the regulation of estrogen and its receptor on the downstream target gene, breast cancer metastasis suppressor 1 (BRMS1) in MCF-7, SKBR3, TTU-1 and MDA-MB-231 breast cancer cells. Our results showed that estrogen increased the transcription and expression of BRMS1 in the ERα positive breast cancer cell line, MCF-7. Additionally, the ERα specific agonist PPT also induced the transcription and expression of BRMS1. However, the two remaining estrogen receptor (ER) subtype agonists had no effect on BRMS1 expression. In order to further examine the influence of ERα on BRMS1 expression, ERα expression was knocked down using siRNA (siERα). Western blot analysis showed that siERα reduced estrogen-induced and PPT-induced BRMS1 expression. In summary, this study demonstrates estrogen, via its α receptor, positively regulates the expression of BRMS1, providing new insight into a potential inhibitory effect of estrogen on metastasis suppression.

Structure-based design of novel chemical modification of the 3'-overhang for optimization of short interfering RNA performance.

Short interfering RNAs (siRNAs) are broadly used to manipulate gene expression in mammalian cells. Although chemical modification is useful for increasing the potency of siRNAs in vivo, rational optimization of siRNA performance through chemical modification is still a challenge. In this work, we designed and synthesized a set of siRNAs containing modified two-nucleotide 3'-overhangs with the aim of strengthening the interaction between the 3'-end of the siRNA strand and the PAZ domain of Ago2. Their efficiency of binding to the PAZ domain was calculated using a computer modeling program, followed by measurement of RNA-Ago2 interaction in a surface plasmon resonance biochemical assay. The results suggest that increasing the level of binding of the 3'-end of the guiding strand with the PAZ domain, and/or reducing the level of binding of the sense strand through modifying the two-nucleotide 3'-overhangs, affects preferential strand selection and improves siRNA activity, while we cannot exclude the possibility that the modifications at the 3'-end of the sense strand may also affect the recognition of the 5'-end of the guiding strand by the MID domain. Taken together, our work presents a strategy for optimizing siRNA performance through asymmetric chemical modification of 3'-overhangs and also helps to develop the computer modeling method for rational siRNA design.

Optical electrocorticogram (OECoG) using wide-field calcium imaging reveals the divergence of neuronal and glial activity during acute rodent seizures.

The role of glia in epilepsy has been widely debated. Using in vivo bulk loading of calcium dyes, we imaged neuronal and glial activity in an acute pharmacologic rodent model of neocortical seizures. Optical calcium-based ECoG maps revealed that neuronal waves propagated rapidly and remained mostly confined to the seizure focus. Glial waves were triggered by ictal onset but propagated slowly in a stereotypical fashion far beyond the seizure focus. Although related at their onset, the divergence of these two phenomena during seizure evolution calls into question their interdependence and the criticality of the role of glia in seizure onset and neurovascular coupling. This article is part of a Special Issue entitled "Status Epilepticus".

Coupling between gamma-band power and cerebral blood volume during recurrent acute neocortical seizures.

Characterization of neural and hemodynamic biomarkers of epileptic activity that can be measured using non-invasive techniques is fundamental to the accurate identification of the epileptogenic zone (EZ) in the clinical setting. Recently, oscillations at gamma-band frequencies and above (>30 Hz) have been suggested to provide valuable localizing information of the EZ and track cortical activation associated with epileptogenic processes. Although a tight coupling between gamma-band activity and hemodynamic-based signals has been consistently demonstrated in non-pathological conditions, very little is known about whether such a relationship is maintained in epilepsy and the laminar etiology of these signals. Confirmation of this relationship may elucidate the underpinnings of perfusion-based signals in epilepsy and the potential value of localizing the EZ using hemodynamic correlates of pathological rhythms. Here, we use concurrent multi-depth electrophysiology and 2-dimensional optical imaging spectroscopy to examine the coupling between multi-band neural activity and cerebral blood volume (CBV) during recurrent acute focal neocortical seizures in the urethane-anesthetized rat. We show a powerful correlation between gamma-band power (25-90 Hz) and CBV across cortical laminae, in particular layer 5, and a close association between gamma measures and multi-unit activity (MUA). Our findings provide insights into the laminar electrophysiological basis of perfusion-based imaging signals in the epileptic state and may have implications for further research using non-invasive multi-modal techniques to localize epileptogenic tissue.

Contralateral dissociation between neural activity and cerebral blood volume during recurrent acute focal neocortical seizures.

OBJECTIVE: Whether epileptic events disrupt normal neurovascular coupling mechanisms locally or remotely is unclear. We sought to investigate neurovascular coupling in an acute model of focal neocortical epilepsy, both within the seizure onset zone and in contralateral homotopic cortex. METHODS: Neurovascular coupling in both ipsilateral and contralateral vibrissal cortices of the urethane-anesthetized rat were examined during recurrent 4-aminopyridine (4-AP, 15 mm, 1 µl) induced focal seizures. Local field potential (LFP) and multiunit spiking activity (MUA) were recorded via two bilaterally implanted 16-channel microelectrodes. Concurrent two-dimensional optical imaging spectroscopy was used to produce spatiotemporal maps of cerebral blood volume (CBV). RESULTS: Recurrent acute seizures in right vibrissal cortex (RVC) produced robust ipsilateral increases in LFP and MUA activity, most prominently in layer 5, that were nonlinearly correlated to local increases in CBV. In contrast, contralateral left vibrissal cortex (LVC) exhibited relatively smaller nonlaminar specific increases in neural activity coupled with a decrease in CBV, suggestive of dissociation between neural and hemodynamic responses. SIGNIFICANCE: These findings provide insights into the impact of epileptic events on the neurovascular unit, and have important implications both for the interpretation of perfusion-based imaging signals in the disorder and understanding the widespread effects of epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

A new dielectric ta-C film coating of Ag-nanoparticle hybrids to enhance TiO2 photocatalysis.

We have demonstrated a novel method to enhance TiO2 photocatalysis by adopting a new ultrathin tetrahedral-amorphous-carbon (ta-C) film coating on Ag nanoparticles to create strong plasmonic near-field enhancement. The result shows that the decomposition rate of methylene blue on the Ag/10 Å ta-C/TiO2 composite photocatalyst is ten times faster than that on a TiO2 photocatalyst and three times faster than that on a Ag/TiO2 photocatalyst. This can be ascribed to the simultaneous realization of two competitive processes: one that excites the surface plasmons (SPs) of the ta-C-film/Ag-nanoparticle hybrid and provides a higher electric field near the ta-C/TiO2 interface compared to Ag nanoparticles alone, while the other takes advantage of the dense diamond-like ta-C layer to help reduce the transfer of photogenerated electrons from the conduction band of TiO2 to the metallic surface, since any electron transfer will suppress the excitation of SP modes in the metal nanoparticles.

Dynamic neurovascular coupling and uncoupling during ictal onset, propagation, and termination revealed by simultaneous in vivo optical imaging of neural activity and local blood volume.

Traditional models of ictal propagation involve the concept of an initiation site and a progressive outward march of activation. The process of neurovascular coupling, whereby the brain supplies oxygenated blood to metabolically active neurons presumably results in a similar outward cascade of hyperemia. However, ictal neurovascular coupling has never been assessed in vivo using simultaneous measurements of membrane potential change and hyperemia with wide spatial sampling. In an acute rat ictal model, using simultaneous intrinsic optical signal (IOS) and voltage-sensitive dye (VSD) imaging of cerebral blood volume and membrane potential changes, we demonstrate that seizures consist of multiple dynamic multidirectional waves of membrane potential change with variable onset sites that spread through a widespread network. Local blood volume evolves on a much slower spatiotemporal scale. At seizure onset, the VSD waves extend beyond the IOS signal. During evolution, spatial correlation with hemodynamic signal only exists briefly at the maximal spread of the VSD signal. At termination, the IOS signal extends spatially and temporally beyond the VSD waves. Hence, vascular reactivity evolves in a separate but parallel fashion to membrane potential changes resulting in a mechanism of neurovascular coupling and uncoupling, which is as dynamic as the seizure itself.

Prevalence of Reproductive Tract Infections and Association with Human Papillomavirus Infection Among Reproductive-Age Women - Six Tertiary Hospitals, China, June 2021-December 2022.

What is already known about this topic?: Previous studies have indicated a possible association between reproductive tract infections (RTIs) and high-risk human papillomavirus (HPV) infection, but the evidence is still inconclusive. What is added by this report?: This multicenter study found significantly higher positive rates of HPV, including general HPV, high-risk HPV, and HPV 16/18 infections, among women who tested positive for single or multiple RTIs compared to women who tested negative for RTIs in gynecological outpatient clinics. What are the implications for public health practice?: Infection with HPV, especially high-risk types, is linked to RTIs and imbalances in the vaginal microbiota. Implementing standardized protocols for identifying and treating RTIs could support the establishment of a healthy vaginal microenvironment. This, in turn, may offer a novel approach to preventing cervical cancer.

Mesoscopic mapping of hemodynamic responses and neuronal activity during pharmacologically induced interictal spikes in awake and anesthetized mice.

Imaging hemodynamic responses to interictal spikes holds promise for presurgical epilepsy evaluations. Understanding the hemodynamic response function is crucial for accurate interpretation. Prior interictal neurovascular coupling data primarily come from anesthetized animals, impacting reliability. We simultaneously monitored calcium fluctuations in excitatory neurons, hemodynamics, and local field potentials (LFP) during bicuculline-induced interictal events in both isoflurane-anesthetized and awake mice. Isoflurane significantly affected LFP amplitude but had little impact on the amplitude and area of the calcium signal. Anesthesia also dramatically blunted the amplitude and latency of the hemodynamic response, although not its area of spread. Cerebral blood volume change provided the best spatial estimation of excitatory neuronal activity in both states. Targeted silencing of the thalamus in awake mice failed to recapitulate the impact of anesthesia on hemodynamic responses suggesting that isoflurane's interruption of the thalamocortical loop did not contribute either to the dissociation between the LFP and the calcium signal nor to the alterations in interictal neurovascular coupling. The blood volume increase associated with interictal spikes represents a promising mapping signal in both the awake and anesthetized states.

Imaging preictal hemodynamic changes in neocortical epilepsy.

OBJECT: The ability to predict seizure occurrence is extremely important to trigger abortive therapies and to warn patients and their caregivers. Optical imaging of hemodynamic parameters such as blood flow, blood volume, and tissue and hemoglobin oxygenation has already been shown to successfully localize epileptic events with high spatial and temporal resolution. The ability to actually predict seizure occurrence using hemodynamic parameters is less well explored. METHODS: In this article, the authors critically review data from the literature on neocortical epilepsy and optical imaging, and they discuss the preictal hemodynamic changes and their application in neurosurgery. RESULTS: Recent optical mapping studies have demonstrated preictal hemodynamic changes in both human and animal neocortex. CONCLUSIONS: Optical measurements of blood flow and oxygenation may become increasingly important for predicting and localizing epileptic events. The ability to successfully predict ictal onsets may be useful to trigger closed-loop abortive therapies.

The more ambidexterity the better? The moderating effect of organizational learning between high-performance HR practices and organizational performance.

Objective: The objective of this study is to test the directly impact of high-performance HR practices on organizational performance, and the mediating effect of organizational ambidexterity empirically. Moreover, the moderating role of organizational learning in the relationship between ambidexterity and specialization in exploitation or exploration on firm performance has also been examined. Ultimately, we construct a moderated mediation model. Methods: Questionnaires were distributed to the target enterprises mainly through the contacts of the research group members, the local management consulting association and the training opportunities for leaders. Finally, a total of 347 CEO questionnaire data were collected from Chinese SMEs. The sample cover Shanghai, Beijing, Chongqing, Jiangsu, Zhejiang, Guangdong, Henan, Sichuan and other eastern and central regions. SPSS 23.0 and AMOS 24.0 were used to analyze the data. Results: The results revealed that high-performance HR practices had a positive effect on organizational performance and that organizational ambidexterity played a partially mediating role between high-performance HR practices and organizational performance. Further, organizational learning moderated the effects of organizational ambidexterity and organizational specificity on firm performance. Discussion: This study provided valuable practical insights. On one hand, this study provides a concrete operational scheme for SMEs in China to realize organizational ambidexterity by integrating a series of HR practices such as employees' ability, motivation and opportunity. On the other hand, through organizational ambidexterity, firms can not only obtain organizational long-term performance by enhancing their new product R & D capabilities, that is, exploratory innovation, but also utilize their existing resources to improve and expand their existing products and services, that is, to achieve short-term performance by exploitative innovation.

Study on mechanism of Zhenwu Decoction in treatment of heart failure based on network pharmacology: A review.

To explore the mechanism of Zhenwu Decoction (ZWD) in the treatment of heart failure (HF) by network pharmacology analysis, so as to provide a basis for the innovation and application of drugs. The effective components and targets of 5 Chinese herbal medicines in ZWD were retrieved by TCM Pharmacology Database and Analysis Platform (TCMSP).Gene card, OMIM and TTD databases were used to obtain the disease targets of HF, and the intersection with the targets of ZWD was obtained. We used Cytoscape3.9.1 software to construct a drug-active component-disease-target interaction network for ZWD treatment of HF, and performed protein-protein interaction (PPI) network and topology analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed. Fifty-nine effective components and 229 targets of ZWD were screened. Among them, ZWD for HF has 27 active components and 38 common targets, and the core targets of PPI are IL-6, ATK1 and TNF. Pathway enrichment analysis included lipid and atherosclerotic and TNF signaling pathways. This study preliminarily clarified the main active components, targets and related pathways of ZWD in the treatment of HF, and laid a foundation for further study of the pharmacological effects of ZWD.