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Mechanistic investigation of host-microbe interactions in the human gut are hindered by difficulty of co-culturing microbes with intestinal epithelial cells. On one hand the gut bacteria are a mix of facultative, aerotolerant or obligate anaerobes, while the intestinal epithelium requires oxygen for growth and function. Thus, a coculture system that can recreate these contrasting oxygen requirements is critical step towards our understanding microbial-host interactions in the human gut. Here, we demonstrate Intestinal Organoid Physoxic Coculture (IOPC) system, a simple and cost-effective method for coculturing anaerobic intestinal bacteria with human intestinal organoids (HIOs). Using commensal anaerobes with varying degrees of oxygen tolerance, such as nano-aerobe Bacteroides thetaiotaomicron and strict anaerobe Blautia sp., we demonstrate that IOPC can successfully support 24–48 hours HIO-microbe coculture. The IOPC recapitulates the contrasting oxygen conditions across the intestinal epithelium seen in viv o. The IOPC cultured HIOs showed increased barrier integrity, and induced expression of immunomodulatory genes. A transcriptomic analysis suggests that HIOs from different donors show differences in the magnitude of their response to coculture with anaerobic bacteria. Thus, the IOPC system provides a robust coculture setup for investigating host-microbe interactions in complex, patient-derived intestinal tissues, that can facilitate the study of mechanisms underlying the role of the microbiome in health and disease.

A generative adversarial network (GAN) makes it possible to map a data sample from one domain to another one. It has extensively been employed in image-to-image and text-to image translation. We propose an EEG-to-EEG translation model to map the scalp-mounted EEG (scEEG) sensor signals to intracranial EEG (iEEG) sensor signals recorded by foramen ovale sensors inserted into the brain. The model is based on a GAN structure in which a conditional GAN (cGAN) is combined with a variational autoencoder (VAE), named as VAE-cGAN. scEEG sensors are plagued by noise and suffer from low resolution. On the other hand, iEEG sensor recordings enjoy high resolution. Here, we consider the task of mapping the scEEG sensor information to iEEG sensors to enhance the scEEG resolution. In this study, our EEG data contain epileptic interictal epileptiform discharges (IEDs). The identification of IEDs is crucial in clinical practice. Here, the proposed VAE-cGAN is firstly employed to map the scEEG to iEEG. Then, the IEDs are detected from the resulting iEEG. Our model achieves a classification accuracy of 76%, an increase of, respectively, 11%, 8%, and 3% over the previously proposed least-square regression, asymmetric autoencoder, and asymmetric–symmetric autoencoder mapping models.

A green-blue infrastructure is essential for achieving the European Green Deal objectives and can be used to protect large cities and their metropolitan areas against urban sprawl. Green-blue infrastructure is an important research topic, because green-blue planning networks provide solutions for mitigating contemporary growing urban and climate challenges. Our study aims to create an innovative methodology for defining and analyzing the elements of green-blue infrastructure and their connectivity within Bucharest, Romania and its metropolitan area, to serve as a planning model. The methodology consists of merging European geodata sets with metropolitan and local data, using GIS tools, and analyzing the connectivity within the study area. All connections resulted from implementing the Linkage Mapper tool were operationalized, using high-resolution satellite images and correcting obtained connections, so that deviations from reality were minimized. The results consist of a conceptual model for planning the green-blue infrastructure within Bucharest and in its metropolitan area, embedding an analysis of its connectivity. The study contributes to implementing the concept of green infrastructure in urban and spatial planning, providing tools for planning the green-blue infrastructures of large cities and their metropolitan areas and, implicitly, reducing urban sprawl, improving air quality and mitigating environmental threats due to climate change.

Focal seizures are episodes of pathological brain activity that appear to arise from a localised area of the brain. The onset patterns of focal seizure activity have been studied intensively, and they have largely been distinguished into two types-low amplitude fast oscillations (LAF), or high amplitude spikes (HAS). Here we explore whether these two patterns arise from fundamentally different mechanisms. Here, we use a previously established computational model of neocortical tissue, and validate it as an adequate model using clinical recordings of focal seizures. We then reproduce the two onset patterns in their most defining properties and investigate the possible mechanisms underlying the different focal seizure onset patterns in the model. We show that the two patterns are associated with different mechanisms at the spatial scale of a single ECoG electrode. The LAF onset is initiated by independent patches of localised activity, which slowly invade the surrounding tissue and coalesce over time. In contrast, the HAS onset is a global, systemic transition to a coexisting seizure state triggered by a local event. We find that such a global transition is enabled by an increase in the excitability of the \"healthy\" surrounding tissue, which by itself does not generate seizures, but can support seizure activity when incited. In our simulations, the difference in surrounding tissue excitability also offers a simple explanation of the clinically reported difference in surgical outcomes. Finally, we demonstrate in the model how changes in tissue excitability could be elucidated, in principle, using active stimulation. Taken together, our modelling results suggest that the excitability of the tissue surrounding the seizure core may play a determining role in the seizure onset pattern, as well as in the surgical outcome.

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.

BackgroundInterleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8+ T and natural killer (NK) cells. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and IL-15 receptor alpha chains (hetIL-15). Several preclinical models support the antitumor activity of hetIL-15 promoting its application in clinical trials.MethodsThe antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays.ResultshetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8+ T cell tumoral infiltration with an increased CD8+/Treg ratio were found by flow cytometry and IHC in hetIL-15 treated animals. Intratumoral NK and CD8+ T cells showed activation features with enhanced interferon-γ (IFN-γ) production, proliferation (Ki67+), cytotoxic potential (Granzyme B+) and expression of the survival factor Bcl-2. Transcriptomics and proteomics analyses revealed complex effects on the tumor microenvironment triggered by hetIL-15 therapy, including increased levels of IFN-γ and XCL1 with intratumoral accumulation of XCR1+IRF8+CD103+ conventional type 1 dendritic cells (cDC1). Concomitantly, the production of the chemokines CXCL9 and CXCL10 by tumor-localized myeloid cells, including cDC1, was boosted by hetIL-15 in an IFN-γ-dependent manner. An increased frequency of circulating CXCR3+ NK and CD8+ T cells was found, suggesting their ability to migrate toward the tumors following the CXCL9 and CXCL10 chemokine gradient.ConclusionsOur results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of immunotherapy interventions. Our study further supports the incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu.

Studying green urban infrastructure is important because of its ecosystem services, contributing to the welfare and comfort of citizens, mitigation of climate changes, and sustainability goals. Urban planning can increase or diminish the performance of ecosystem services. Despite numerous studies on the green infrastructure–services–planning nexus, there are very few concrete planning recommendations. This study aims to provide such recommendations for a broader audience by analyzing the dynamic of open green areas in Polish and Romanian cities, connected with its drivers. A novel approach including mathematical modeling and geostatistical analyses was applied to Urban Atlas and statistical yearbooks data. The results indicated that open green areas were lost and fragmented in all Romanian and Polish cities during 2006–2018. The drivers included urban built-up areas, population and density, the number of building permits, number of new dwellings completed, number of employees, and total length of roads. The study also revealed a tremendous lack of consistent datasets across the countries using the same statistical indicators. Based on the findings, planners should aim to preserve and develop urban greenery and maintain its continuity. City managers should use more research and decision-making policy developers to develop targeted policies and scientists should develop planning manuals.

Besides decades of research showing the role of the medial temporal lobe (MTL) in memory and the encoding of associations, the neural substrates underlying these functions remain unknown. We identified single neurons in the human MTL that responded to multiple and, in most cases, associated stimuli. We observed that most of these neurons exhibit no differences in their spike and local field potential (LFP) activity associated with the individual response-eliciting stimuli. In addition, LFP responses in the theta band preceded single neuron responses by ~70 ms, with the single trial phase providing fine tuning of the spike response onset. We postulate that the finding of similar neuronal responses to associated items provides a simple and flexible way of encoding memories in the human MTL, increasing the effective capacity for memory storage and successful retrieval. In this work, the authors recorded single neurons and field potentials from the human medial temporal lobe (MTL) and show indistinguishable responses to associated stimuli. This coding mechanism provides a simple and flexible way of encoding memories in the human MTL.

Planning for a green–blue infrastructure system around big cities, having the shape of a belt, to connect natural areas—such as green spaces, water, and agricultural land—is a solution for mitigating the challenges of climate change and urban sprawl. In this context, this study presents an innovative information technology solution for assessing the connectivity of the green and blue areas in the metropolitan area of Bucharest, Romania. The solution is to try to stop the sprawl of Bucharest into the adjacent rural areas and answer the need for a green infrastructure providing ecosystem services. The methodology uses datasets compatible with the European databases on environmental issues, CORINE Land Cover 2018 and Urban Atlas, and two tools in the ArcGIS PRO 2.9 software package, namely Cost Raster and Cost Connectivity. Based on the results, we developed a framework for implementing a strategy for the green–blue infrastructure for the Bucharest metropolitan area. Our methodology is a starter for planning a green–blue belt for the metropolitan area of Bucharest and a model of good practice in terms of making green–blue infrastructure part of urban and territorial planning.

Recent studies carried out by landscape and urban ecologists have shown that habitat fragmentation has negative environmental effects and is accountable for the loss of biodiversity. The development and extension of road infrastructure to support economic growth, the urbanization and the land-use changes are major drivers of habitat fragmentation. Planners have attempted to develop tools for restoring connectivity and stopping biodiversity loss at the landscape scale and which can be applied at the urban scale, too. The study fills in the gap by developing a methodology for identifying the ecological corridors of a Romanian large carnivore (brown bear) in the Romanian Carpathian Mountains at several spatial scales. The methodology relies on geospatial data; this is equally its most important advantage and challenge. Our findings suggest that the implementation of ecological corridors in current planning practice must be completed cautiously, provided the possible restrictions are imposed on economic activities by plans, and highlight the importance of field data in increasing the scientific soundness of the results. In addition, the findings show the need to interconnect spatial planning policies with environmental policies by improving the actual legislation.