Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions.

The estrogen receptor (ER), glucocorticoid receptor (GR), and forkhead box protein 1 (FoxA1) are significant factors in breast cancer progression. FoxA1 has been implicated in establishing ER-binding patterns though its unique ability to serve as a pioneer factor. However, the molecular interplay between ER, GR, and FoxA1 requires further investigation. Here we show that ER and GR both have the ability to alter the genomic distribution of the FoxA1 pioneer factor. Single-molecule tracking experiments in live cells reveal a highly dynamic interaction of FoxA1 with chromatin in vivo. Furthermore, the FoxA1 factor is not associated with detectable footprints at its binding sites throughout the genome. These findings support a model wherein interactions between transcription factors and pioneer factors are highly dynamic. Moreover, at a subset of genomic sites, the role of pioneer can be reversed, with the steroid receptors serving to enhance binding of FoxA1.

An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors.

Transcription factors (TFs) regulate gene expression by binding to specific consensus motifs within the local chromatin context. The mechanisms by which TFs navigate the nuclear environment as they search for binding sites remain unclear. Here, we used single-molecule tracking and machine-learning-based classification to directly measure the nuclear mobility of the glucocorticoid receptor (GR) in live cells. We revealed two distinct and dynamic low-mobility populations. One accounts for specific binding to chromatin, while the other represents a confinement state that requires an intrinsically disordered region (IDR), implicated in liquid-liquid condensate subdomains. Further analysis showed that the dwell times of both subpopulations follow a power-law distribution, consistent with a broad distribution of affinities on the GR cistrome and interactome. Together, our data link IDRs with a confinement state that is functionally distinct from specific chromatin binding and modulates the transcriptional output by increasing the local concentration of TFs at specific sites.

Transcriptional Bursting and Co-bursting Regulation by Steroid Hormone Release Pattern and Transcription Factor Mobility.

Genes are transcribed in a discontinuous pattern referred to as RNA bursting, but the mechanisms regulating this process are unclear. Although many physiological signals, including glucocorticoid hormones, are pulsatile, the effects of transient stimulation on bursting are unknown. Here we characterize RNA synthesis from single-copy glucocorticoid receptor (GR)-regulated transcription sites (TSs) under pulsed (ultradian) and constant hormone stimulation. In contrast to constant stimulation, pulsed stimulation induces restricted bursting centered around the hormonal pulse. Moreover, we demonstrate that transcription factor (TF) nuclear mobility determines burst duration, whereas its bound fraction determines burst frequency. Using 3D tracking of TSs, we directly correlate TF binding and RNA synthesis at a specific promoter. Finally, we uncover a striking co-bursting pattern between TSs located at proximal and distal positions in the nucleus. Together, our data reveal a dynamic interplay between TF mobility and RNA bursting that is responsive to stimuli strength, type, modality, and duration.

Differences in temporal processing speeds between the right and left auditory cortex reflect the strength of recurrent synaptic connectivity.

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

On-demand low-frequency stimulation for seizure control: efficacy and behavioural implications.

Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults, is often refractory to medication and associated with hippocampal sclerosis. Deep brain stimulation represents an alternative treatment option for drug-resistant patients who are ineligible for resective brain surgery. In clinical practice, closed-loop stimulation at high frequencies is applied to interrupt ongoing seizures, yet has (i) a high incidence of false detections; (ii) the drawback of delayed seizure-suppressive intervention; and (iii) limited success in sclerotic tissue. As an alternative, low-frequency stimulation (LFS) has been explored recently in patients with focal epilepsies. In preclinical epilepsy models, hippocampal LFS successfully prevented seizures when applied continuously. Since it would be advantageous to reduce the stimulation load, we developed a protocol for on-demand LFS. Given the importance of the hippocampus for navigation and memory, we investigated potential consequences of LFS on hippocampal function. To this end, we used the intrahippocampal kainate mouse model, which recapitulates the key features of MTLE, including spontaneous seizure activity and hippocampal sclerosis. Specifically, our online detection algorithm monitored epileptiform activity in hippocampal local field potential recordings and identified short epileptiform bursts preceding focal seizure clusters, triggering hippocampal LFS to stabilize the network state. To probe behavioural performance, we tested the acute influence of LFS on anxiety-like behaviour in the light-dark box test, spatial and non-spatial memory in the object location memory and novel object recognition test, as well as spatial navigation and long-term memory in the Barnes maze. On-demand LFS was almost as effective as continuous LFS in preventing focal seizure clusters but with a significantly lower stimulation load. When we compared the behavioural performance of chronically epileptic mice to healthy controls, we found that both groups were equally mobile, but epileptic mice displayed an increased anxiety level, altered spatial learning strategy and impaired memory performance. Most importantly, with the application of hippocampal LFS before behavioural training and test sessions, we could rule out deleterious effects on cognition and even show an alleviation of deficits in long-term memory recall in chronically epileptic mice. Taken together, our findings may provide a promising alternative to current therapies, overcoming some of their major limitations, and inspire further investigation of LFS for seizure control in focal epilepsy syndromes.

Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.

Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer. Advances in high-throughput sequencing technologies have accelerated the identification of somatic and germline single nucleotide mutations in non-coding genomic regions. This review provides an overview of somatic and germline non-coding single nucleotide alterations affecting transcription factor binding sites in GREs, specifically involved in cancer biology. It also summarizes the technologies available for exploring GREs and the challenges associated with studying and characterizing non-coding single nucleotide mutations. Understanding the role of GRE alterations in cancer is essential for improving diagnostic and prognostic capabilities in the precision medicine era, leading to enhanced patient-centered clinical outcomes.

Consciousness is supported by near-critical slow cortical electrodynamics.

Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, we empirically identify a mathematically specific critical point near which waking cortical oscillatory dynamics operate, which is known as the edge-of-chaos critical point, or the boundary between stability and chaos. We do so by applying the recently developed modified 0-1 chaos test to electrocorticography (ECoG) and magnetoencephalography (MEG) recordings from the cortices of humans and macaques across normal waking, generalized seizure, anesthesia, and psychedelic states. Our evidence suggests that cortical information processing is disrupted during unconscious states because of a transition of low-frequency cortical electric oscillations away from this critical point; conversely, we show that psychedelics may increase the information richness of cortical activity by tuning low-frequency cortical oscillations closer to this critical point. Finally, we analyze clinical electroencephalography (EEG) recordings from patients with disorders of consciousness (DOC) and show that assessing the proximity of slow cortical oscillatory electrodynamics to the edge-of-chaos critical point may be useful as an index of consciousness in the clinical setting.

The CHARGE syndrome ortholog CHD-7 regulates TGF-ß pathways in Caenorhabditis elegans.

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. Despite the public health relevance of this disorder, relevant cellular pathways and targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of Chd7, is required for dauer morphogenesis, lifespan determination, stress response, and body size determination. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the DAF-7/ tumor growth factor-ß (TGF-ß) pathway. Epistatic analysis places CHD-7 at the level of the DAF-3/DAF-5 complex, but we found that CHD-7 also directly impacts the expression of multiple components of this pathway. Transcriptomic analysis revealed that chd-7 mutants fail to repress daf-9 for execution of the dauer program. In addition, CHD-7 regulates the DBL-1/BMP pathway components and shares roles in male tail development and cuticle synthesis. To explore a potential conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino-mediated knockdown of Chd7 led to a reduction in col2a1 messenger RNA (mRNA) levels, a collagen whose expression depends on TGF-ß signaling. Both embryonic lethality and craniofacial defects in Chd7-depleted tadpoles were partially rescued by overexpression of col2a1 mRNA. We suggest that Chd7 has conserved roles in regulation of the TGF-ß signaling pathway and pathogenic Chd7 could lead to a defective extracellular matrix deposition.

Total Sleep Deprivation Increases Brain Age Prediction Reversibly in Multisite Samples of Young Healthy Adults.

Sleep loss pervasively affects the human brain at multiple levels. Age-related changes in several sleep characteristics indicate that reduced sleep quality is a frequent characteristic of aging. Conversely, sleep disruption may accelerate the aging process, yet it is not known what will happen to the age status of the brain if we can manipulate sleep conditions. To tackle this question, we used an approach of brain age to investigate whether sleep loss would cause age-related changes in the brain. We included MRI data of 134 healthy volunteers (mean chronological age of 25.3 between the age of 19 and 39 years, 42 females/92 males) from five datasets with different sleep conditions. Across three datasets with the condition of total sleep deprivation (>24 h of prolonged wakefulness), we consistently observed that total sleep deprivation increased brain age by 1-2 years regarding the group mean difference with the baseline. Interestingly, after one night of recovery sleep, brain age was not different from baseline. We also demonstrated the associations between the change in brain age after total sleep deprivation and the sleep variables measured during the recovery night. By contrast, brain age was not significantly changed by either acute (3 h time-in-bed for one night) or chronic partial sleep restriction (5 h time-in-bed for five continuous nights). Together, the convergent findings indicate that acute total sleep loss changes brain morphology in an aging-like direction in young participants and that these changes are reversible by recovery sleep.SIGNIFICANCE STATEMENT Sleep is fundamental for humans to maintain normal physical and psychological functions. Experimental sleep deprivation is a variable-controlling approach to engaging the brain among different sleep conditions for investigating the responses of the brain to sleep loss. Here, we quantified the response of the brain to sleep deprivation by using the change of brain age predictable with brain morphologic features. In three independent datasets, we consistently found increased brain age after total sleep deprivation, which was associated with the change in sleep variables. Moreover, no significant change in brain age was found after partial sleep deprivation in another two datasets. Our study provides new evidence to explain the brainwide effect of sleep loss in an aging-like direction.

Structural basis of metallo-ß-lactamase resistance to taniborbactam.

The design of inhibitors against metallo-ß-lactamases (MBLs), the largest family of carbapenemases, has been a strategic goal in designing novel antimicrobial therapies. In this regard, the development of bicyclic boronates, such as taniborbactam (TAN) and xeruborbactam, is a major achievement that may help in overcoming the threat of MBL-producing and carbapenem-resistant Gram-negative pathogens. Of concern, a recent report has shown that New Delhi MBL-9 (NDM-9) escapes the inhibitory action of TAN by a single amino acid substitution with respect to New Delhi MBL-1 (NDM-1), the most widely disseminated MBL. Here, we report a docking and computational analysis that identifies that "escape variants" against TAN can arise by disruption of the electrostatic interaction of negative charges in the active site loops of MBLs with the N-(2-aminoethyl)cyclohexylamine side chain of TAN. These changes result in non-productive binding modes of TAN that preclude reaction with the MBLs, a phenomenon that is not restricted to NDM-9. This analysis demonstrates that single amino acid substitutions in non-essential residues in MBL loops can unexpectedly elicit resistance to TAN.

Structural role of K224 in taniborbactam inhibition of NDM-1.

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid ß-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-ß-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ). We hypothesized that substitutions at K224, the homologous position in NDM-1, could impact FEP/TAN resistance. To evaluate this, a library of codon-optimized NDM K224X clones for minimum inhibitory concentration (MIC) measurements was constructed; steady-state kinetics and molecular docking simulations were next performed. Surprisingly, our investigation revealed that the addition of TAN restored FEP susceptibility only for NDM-1, as the MICs for the other 19 K224X variants remained comparable to those of FEP alone. Moreover, compared to NDM-1, all K224X variants displayed significantly lower MICs for imipenem, tebipenem, and cefiderocol (32-, 133-, and 33-fold lower, respectively). In contrast, susceptibility to CAZ was mostly unaffected. Kinetic assays with the K224I variant, the only variant with hydrolytic activity to FEP comparable to NDM-1, confirmed that the inhibitory capacity of TAN was modestly compromised (IC50 0.01 µM vs 0.14 µM for NDM-1). Lastly, structural modeling and docking simulations of TAN in NDM-1 and in the K224I variant revealed that the hydrogen bond between TAN's carboxylate with K224 is essential for the productive binding of TAN to the NDM-1 active site. In addition to the report of NDM-9 (E149K) as FEP/TAN resistant, this study demonstrates the fundamental role of single amino acid substitutions in the inhibition of NDM-1 by TAN.

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Chromatin structure and dynamics: one nucleosome at a time.

Eukaryotic genomes store information on many levels, including their linear DNA sequence, the posttranslational modifications of its constituents (epigenetic modifications), and its three-dimensional folding. Understanding how this information is stored and read requires multidisciplinary collaborations from many branches of science beyond biology, including physics, chemistry, and computer science. Concurrent recent developments in all these areas have enabled researchers to image the genome with unprecedented spatial and temporal resolution. In this review, we focus on what single-molecule imaging and tracking of individual proteins in live cells have taught us about chromatin structure and dynamics. Starting with the basics of single-molecule tracking (SMT), we describe some advantages over in situ imaging techniques and its current limitations. Next, we focus on single-nucleosome studies and what they have added to our current understanding of the relationship between chromatin dynamics and transcription. In celebration of Robert Feulgen's ground-breaking discovery that allowed us to start seeing the genome, we discuss current models of chromatin structure and future challenges ahead.

Ecological transcriptomics reveals stress response pathways of a ground-herb species in a waterlogging gradient of Amazonian riparian forests.

Environmental stress is a fundamental facet of life and a significant driver of natural selection in the wild. Gene expression diversity may facilitate adaptation to environmental changes, without necessary genetic change, but its role in adaptive divergence remains largely understudied in Neotropical systems. In Amazonian riparian forests, species distribution is predominantly influenced by species' waterlogging tolerance. The flooding gradient delineates distinct wetland forest types, shaping habitats and species characteristics. Here we investigated the molecular basis of environmental stress response in a tropical ground-herb species (Ischnosiphon puberulus) to environmental variation in Amazonian riparian forests. We compared environmental variables and gene expression profiles from individuals collected in two forest types: Igapó and Terra firme in the Amazonian riparian forests. Predictable seasonal flooding poses a significant challenge in Igapó compared to Terra firme environments, with the former presenting higher water column height and longer flooding duration. Our findings suggest that contrasting environmental conditions related to flooding regimes are important drivers of population genetic differentiation and differential gene expression in I. puberulus. Enriched gene ontology terms highlight associations with environmental stresses, such as defence response, water transport, phosphorylation, root development, response to auxin, salicylic acid and oxidative stress. By uncovering key environmental stress response pathways conserved across populations, I. puberulus offers novel genetic insights into the molecular basis of plant reactions to environmental constraints found in flooded areas of this highly biodiverse neotropical ecosystem.

Beneath the blooms: Unearthing the effect of rhizospheric bacteria on floral signals and pollinator preferences.

The relationship between plants and pollinators is known to be influenced by ecological interactions with other community members. While most research has focused on aboveground communities affecting plant-pollinator interactions, it is increasingly recognized that soil-dwelling organisms can directly or indirectly impact these interactions. Although studies have examined the effects of arbuscular mycorrhizal fungi on floral traits, there is a gap in research regarding similar effects associated with plant growth-promoting rhizobacteria (PGPR), particularly concerning floral scent. Our study aimed to investigate the influence of the PGPR Bacillus amyloliquefaciens on the floral traits of wild (Solanum habrochaites, Solanum pimpinellifolium and Solanum peruvianum) and cultivated tomato (Solanum lycopersicum), as well as the impact of microbially-driven changes in floral scent on the foraging behaviour of the stingless bee Melipona quadrifasciata. Our findings revealed that inoculating tomatoes with PGPR led to an increased number of flowers and enhanced overall floral volatile emission. Additionally, we observed higher flower biomass and pollen levels in all species, except S. peruvianum. Importantly, these changes in volatile emissions influenced the foraging behaviour of M. quadrifasciata significantly. Our results highlight the impact of beneficial soil microbes on plant-pollinator interactions, shedding light on the multiple effects that plant-microbial interactions can have on aboveground organisms.

EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

Generalist versus Specialist Self-Replicators.

Darwinian evolution, including the selection of the fittest species under given environmental conditions, is a major milestone in the development of synthetic living systems. In this regard, generalist or specialist behavior (the ability to replicate in a broader or narrower, more specific food environment) are of importance. Here we demonstrate generalist and specialist behavior in dynamic combinatorial libraries composed of a peptide-based and an oligo(ethylene glycol) based building block. Three different sets of macrocyclic replicators could be distinguished based on their supramolecular organization: two prepared from a single building block as well as one prepared from an equimolar mixture of them. Peptide-containing hexamer replicators were found to be generalists, i. e. they could replicate in a broad range of food niches, whereas the octamer peptide-based replicator and hexameric ethyleneoxide-based replicator were proven to be specialists, i. e. they only replicate in very specific food niches that correspond to their composition. However, sequence specificity cannot be demonstrated for either of the generalist replicators. The generalist versus specialist nature of these replicators was linked to their supramolecular organization. Assembly modes that accommodate structurally different building blocks lead to generalist replicators, while assembly modes that are more restrictive yield specialist replicators.

Concentration-effect relationships of plasma caffeine on EEG delta power and cardiac autonomic activity during human sleep.

Acute caffeine intake affects brain and cardiovascular physiology, yet the concentration-effect relationships on the electroencephalogram and cardiac autonomic activity during sleep are poorly understood. To tackle this question, we simultaneously quantified the plasma caffeine concentration with ultra-high-performance liquid chromatography, as well as the electroencephalogram, heart rate and high-frequency (0.15-0.4 Hz) spectral power in heart rate variability, representing parasympathetic activity, with standard polysomnography during undisturbed human sleep. Twenty-one healthy young men in randomized, double-blind, crossover fashion, ingested 160 mg caffeine or placebo in a delayed, pulsatile-release caffeine formula at their habitual bedtime, and initiated a 4-hr sleep opportunity 4.5 hr later. The mean caffeine levels during sleep exhibited high individual variability between 0.2 and 18.4 µmol L-1 . Across the first two non-rapid-eye-movement (NREM)-rapid-eye-movement sleep cycles, electroencephalogram delta (0.75-2.5 Hz) activity and heart rate were reliably modulated by waking and sleep states. Caffeine dose-dependently reduced delta activity and heart rate, and increased high-frequency heart rate variability in NREM sleep when compared with placebo. The average reduction in heart rate equalled 3.24 ± 0.77 beats per minute. Non-linear statistical models suggest that caffeine levels above ~7.4 µmol L-1 decreased electroencephalogram delta activity, whereas concentrations above ~4.3 µmol L-1 and ~ 4.9 µmol L-1 , respectively, reduced heart rate and increased high-frequency heart rate variability. These findings provide quantitative concentration-effect relationships of caffeine, electroencephalogram delta power and cardiac autonomic activity, and suggest increased parasympathetic activity during sleep after intake of caffeine.

EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond.

Immune Competence and Pain: A Narrative Review.

PURPOSE OF REVIEW: This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management. RECENT FINDINGS: In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy.