Abstract: Fertilization strategies are pivotal in sustainable agriculture, affecting both soil health and crop quality. This study investigated the impact of a circular fertilization approach based on agro-industrial residues—specifically a blend of sulphur bentonite and orange pro-cessing waste (RecOrgFert PLUS)—on soil physicochemical and biological properties, as well as the nutritional and nutraceutical quality of broccoli (Brassica oleracea var. italica) grown in Mediterranean conditions (Condofuri, Southern Italy). The effects of RecOrgFert PLUS were compared with those of a synthetic NPK fertilizer, an organic fertilizer (horse manure), and an unfertilized control. Results demonstrated that RecOrgFert PLUS signif-icantly improved soil organic carbon (3.37%), microbial biomass carbon (791 μg C g⁻¹), and key enzymatic activities, indicating enhanced soil biological functioning. Broccoli cultivated under RecOrgFert PLUS also exhibited the highest concentrations of health-promoting compounds, including total phenols (48.87 mg GAE g⁻¹), vitamin C (51.93 mg ASA 100 g⁻¹), and total proteins (82.45 mg BSA g⁻¹). This work provides novel evidence that combining elemental sulphur with orange processing waste not only re-stores soil fertility but also boosts the nutraceutical and nutritional value of food crops. Unlike previous studies focusing on soil or plant yield alone, this study uniquely inte-grates soil health indicators with bioactive compound accumulation in broccoli, high-lighting the potential of circular bio-based fertilization in functional food production and Mediterranean agroecosystem sustainability.

Abstract: The human gut microbiota, a complex ecosystem of microorganisms, is intricately linked to health and aging. While numerous studies have explored age-related changes in the gut microbiome of healthy individuals, the impact of aging on this microbial community in individuals with pre-existing gastrointestinal conditions remains largely uncharted. This study aimed to investigate how aging affects the ecological and genetic characteristics of the gut microbiome in individuals with gastrointestinal disorders. Using an in-house bioinformatic pipeline PanOmiQ, we analyzed fecal samples from 54 individuals with gastrointestinal conditions and compared them to a healthy control group. Our results revealed significant ecological differences between age groups and healthy controls, particularly in alpha and beta diversity and relative abundance at the phylum level. However, we found no clear evidence of age-related genetic variation within microbial species. These findings underscore the unique ecological dynamics of the gut microbiome in individuals with gastrointestinal disorders and suggest that aging may play a role in shaping the composition of specific microbial groups, such as Proteobacteria and Archaea. Further research is needed to elucidate the specific functions of these microbial groups in the aging gut and to explore potential therapeutic interventions for improving gut health in gastrointestinal-compromised individuals.

Abstract: This study examines the impact of recent climatic trends on the preservation of submerged wooden structures at the Gran Carro archaeological site in Lake Bolsena, Italy. Climatic data from the Bolsena Meteorological Station were analysed alongside in situ water quality measurements collected at a depth of 4 meters near the archaeological remains. Key parameters included water temperature (Tw), redox potential (Eh), dissolved oxygen (DO), and total dissolved solids (TDS). Over the past decade, there has been an increase in days with air temperatures exceeding 30 °C and a general rise in mean temperatures. In 2022 and 2023, elevated air temperatures correlated with increased water temperatures, decreased redox potential, and reduced dissolved oxygen levels. Additionally, high evapotranspiration rates and declining water levels, as confirmed by UAV analyses, suggest intensified stress on the lake ecosystem, particularly due to increased water extraction for irrigation. These conditions may have created an environment with heightened anaerobicity, favouring the activity of erosion bacteria known to degrade submerged wood. Conversely, higher evapotranspiration rates could facilitate oxygen penetration to lower depths, potentially reactivating decay agents such as soft rot fungi and tunnelling bacteria. Overall, these climatic changes appear to have a detrimental effect on the preservation of submerged wooden structures in the lake. Consequently, adaptive management strategies will be necessary to mitigate these impacts and ensure the protection of both the lake environment and the archaeological wooden remains.

Abstract: Motion perception is a fundamental function of tactile system, essential for object exploration and manipulation. While human studies have largely focused on discrete or pulsed stimuli with staggered onsets, many natural tactile signals are continuous and rhythmically patterned. Here, we investigate whether phase differences between simultaneously presented, continuous amplitude-modulated vibrations can induce the perception of motion across fingertips. Participants reliably perceived motion direction at modulation frequencies up to 1Hz, with discrimination performance systematically dependent on the phase lag between vibrations. Critically, trial-level confidence reports revealed lowest certainty for anti-phase (180°) conditions, consistent with stimulus ambiguity as predicted by my mathematical framework. I propose two candidate computational mechanisms for tactile motion processing. The first is a conventional cross-correlation computation over the envelopes; The second is a probabilistic model based on the uncertain detection of temporal reference points (e.g., envelope peaks) within threshold-defined windows. This model, despite having only a single parameter (uncertainty width determined by an amplitude discrimination threshold), accounts for both the non-linear shape and asymmetries of observed psychometric functions. These results demonstrate that the human tactile system can extract directional information from distributed phase-coded signals in the absence of spatial displacement, revealing a motion perception mechanism that parallels arthropod systems but potentially arises from distinct perceptual constraints.

Abstract: Despite the increasing emergence of resistance, insecticide-based tools remain the main strategies used so far for vector control in Africa. In the absence of more effective alternatives, monitoring and screening for new resistance mechanisms remain the main strategies to ensure the continued deployment of current vector control tools. Here, we used the whole genome sequencing data from the Anopheles gambiae 1000 Genomes Project to investigate potential novel insecticide resistance genes in the Anopheles gambiae complex. We used a broad range of genomic data analysis techniques to identify and examine genetic variation in the potential new resistance genes identified. The results showed elevated Garud H12 values in the genomic regions of the 2L chromosome corresponding to the aldehyde oxidase cluster genes (AGAP006220, AGAP006221, AGAP006224, AGAP006225 and AGAP006226). The findings show a high occurrence of the two most common haplotypes in the populations, suggesting a recent selective sweep in this region driven by positive selection. In addition, single nucleotide polymorphisms (SNPs) have been identified in these genes with frequencies up to 100%, including 569, 691, 1433, 978, and 811 non-synonymous SNPs in AGAP006220, AGAP006221, AGAP006224, AGAP006225, and AGAP006226, respectively. Copy number variation (CNVs) such as deletions and amplifications were also identified in these genes at low frequencies (<12%). The analysis of population structure analysis revealed evidence of adaptive and geographic gene flow between An. gambiae and An. coluzzii, confirming the historical connectivity between both species. These findings showed the potential role of aldehyde oxidase genes in the resistance of An. gambiae s.l. populations to insecticides. This study emphasized the importance of genomic surveillance for identifying new potential genes involved in the adaptation of malaria vectors to ecological changes.

Abstract: In this study, the invasive orange spiny whitefly (“OSW”; Aleurocanthus spiniferus) and a species of Encarsia parasitising its puparia were studied in three different areas of the province of Modena (Emilia-Romagna, northern Italy): a pear orchard in Bomporto, an organic pear orchard in Carpi, and the semi-natural botanical garden "La Pica" in San Felice sul Panaro. The material of both species was collected for taxonomic and molecular studies. The abundance of OSW and parasitoid activity was surveyed in whitefly puparia, with a focus on the botanical garden. A total of 1,800 leaves of Malus domestica, Pyrus communis and Vitis vinifera were sampled to assess whitefly infestation. The results showed a significant variation in the abundance of A. spiniferus puparia, with the highest infestation observed in V. vinifera. Morphological and molecular analyses, including mitochondrial COI and rRNA 16S for whiteflies and COI and 28S for parasitoids, confirmed the identity of A. spiniferus and identified the parasitoid as Encarsia nipponica. Molecular data also revealed the presence of three haplotypes of A. spiniferus, including a haplotype from China new to Europe. The parasitisation rate by E. nipponica was low (0.015%). Our results update the distribution of A. spiniferus and E. nipponica in Italy, providing insights into their ecological interactions and potential implications for pest management strategies.

Abstract: Background: The SARS-CoV-2 Omicron variant has become a dominant driver of the COVID-19 pandemic due to its high transmissibility and immune escape potential. Although clinical outcomes are generally mild to moderate, the inflammatory mechanisms triggered by Omicron subvariants remain poorly defined. The goal of this study was to consider both viral evolution and host immune response by assessing plasma cytokine levels in patients infected with SARS-CoV-2 Omicron subvariants. Methods: A total of 115 individuals were recruited, including 40 with laboratory-confirmed SARS-CoV-2 infection by RT-qPCR. Demographic, clinical, and comorbidity data were collected. Plasma levels of IL-6, TNF, IFN-γ, IL-4, IL-2, IL-10, and IL-17A were quantified using Cytometric Bead Array. Subvariant data were obtained from GISAID records and grouped into early (BA.1-lineage) and late (BA.4/BA.5-lineage) Omicron clusters. Statistical analysis included nonparametric and parametric tests, correlation matrices, and multivariate comparisons. Results: Pharyngitis, nasal discharge, cough, and headache were the most common symptoms among infected individuals. Despite no significant variation in symptom distribution across subvariants, infected patients showed higher levels of IFN-γ, TNF, IL-10, IL-4, and IL-2 than non-infected controls (p < 0.05). IL-4 and IL-10 were significantly higher in early Omicron infections. No associations were observed between cytokine levels and comorbidities. A significant correlation was found between reporting fewer symptoms and having received three vaccine doses. Conclusions: Infection with Omicron subvariants elicits a strong but balanced cytokine response. Despite genetic divergence between lineages, immune and clinical patterns remain conserved, with vaccination appearing to mitigate symptom burden.

Abstract: Quantitative proteomics analyses rely on robust statistical methods for differential expression, impacting downstream pathway and functional enrichment. This meta-analysis investigated the influence of Hypothesis Testing Methods (HTMs) and Criteria for Biological Relevance (CBRs) on functional enrichment concordance. Five independent label-free quantitative proteomics datasets were reanalyzed using diverse frequentist (t-test, Limma, DEqMS, MSstats) and a Bayesian (rstanarm) approach. Concordance of enriched terms was assessed using Jaccard indices, categorized by four comparison types: Intra-HTM_FC_CBR, Intra-HTM_Bayes_CBR, Intra-CBR_Fixed_HTM, and Inter-HTM_Inter_CBR. Results showed highly significant differences in Jaccard similarity distributions among comparison types (Kruskal-Wallis p = 5e-04). “Intra-HTM_FC_CBR” exhibited the highest consistency, indicating minor HTM influence when using FC-based CBR. “Intra-CBR_Fixed_HTM” also maintained high concordance, suggesting robust agreement between FC and Bayesian CBRs when HTM is fixed. Conversely, “Intra-HTM_Bayes_CBR” and “Inter-HTM_Inter-CBR” showed the lowest consistency, highlighting the critical impact of Bayesian method choice and mixed comparisons on functional overlaps, particularly for Gene Ontology terms. KEGG pathways displayed more uniform, method-insensitive concordance. Sensitivity analysis confirmed the robustness of these findings. This study underscores that analytical choices profoundly influence functional enrichment outcomes, emphasizing the need for transparency and careful consideration in proteomics research to ensure reproducibility.

Abstract: The bacterial diversity of soils cultivated with avocado (Persea americana M.) is influenced by various factors, perhaps the most determining being the type of agronomic manage-ment used by farmers. In conventional agronomic management (CM), high doses of agro-chemicals such as fungicides and bactericides are applied, which alter the biological fer-tility of the soil, including the bacterial populations present in the rhizosphere. In contrast, in organic agronomic management (OM), the use of agrochemicals is avoided, and organ-ic amendments are applied instead. These amendments contain a large quantity and di-versity of bacteria that may be beneficial for soil remediation and crop nutrition. This re-search aimed to isolate and morphologically characterize rhizospheric bacteria from avo-cado trees under different agronomic management practices (CM and OM). The bacterial isolates were tested for their in vitro plant growth promoting capacity through biochemi-cal assays for phosphorus and calcium solubilization and nitrogen fixation. Additionally, their in vivo effect on the growth of tomato (S. lycopersicum) was evaluated, and their an-tagonistic capacity against Fusarium sp. was assessed. The results showed differences in the quantity, diversity, and morphologies of bacterial isolates depending on the type of agronomic management. Greater diversity was found in OM (Shannon diversity index of 2.44) compared to CM (1.75). Regarding plant growth promotion both in vitro and in vivo, OM isolates showed higher activity and promoted greater tomato growth; these same iso-lates also exhibited antagonistic activity against Fusarium sp. This indicates that OM plots of P. americana presented a greater diversity of bacterial isolates with plant growth-promoting effects and antagonistic activity compared to CM plots, highlighting the impact of agronomic management on soil bacterial populations.

Abstract: As we age or become overweight, certain cells in our bodies stop dividing and enter a state called “senescence.” Although these senescent cells no longer grow, they remain active and release a mix of inflammatory signals (known as SASP) that can harm nearby tissues. In fat, liver, and other organs, this ongoing inflammation makes it harder for cells to use insulin properly, leading to conditions like type 2 diabetes and fatty liver disease. Researchers are exploring drugs that either remove these senescent cells or block their harmful signals, as well as lifestyle changes like exercise and healthy eating, to reduce inflammation and restore normal metabolism. By targeting the root causes of this “toxic” cell behavior, we hope to prevent or treat many age‐related metabolic problems. The accumulation of senescent cells in metabolic tissues—including adipose tissue, liver, pancreas, and skeletal muscle—along with the senescence-associated secretory phenotype (SASP) has emerged as a significant factor in developing chronic inflammation and metabolic dysfunction. Senescent cells, which have stopped dividing but remain metabolically active, secrete a complex mix of pro-inflammatory cytokines, chemokines, proteases, and growth factors. This secretory profile disrupts tissue homeostasis and creates a persistent inflammatory environment, impairing metabolic processes. Consequently, this leads to conditions such as insulin resistance, type 2 diabetes, and obesity-related complications. This review delves into the molecular mechanisms that initiate cellular senescence within metabolic tissues and examines how the ensuing SASP fosters an inflammatory microenvironment, linking senescence to disorders such as insulin resistance, non-alcoholic fatty liver disease, and type 2 diabetes. Additionally, we explore the interplay between environmental stressors, metabolic stress, and the onset of cellular aging, emphasizing how these factors collectively exacerbate the deleterious impact of SASP. Emerging therapeutic strategies are critically evaluated, including senolytics, which selectively target and eliminate senescent cells, and SASP modulators to dampen the harmful secretory milieu. These interventions hold promise for restoring metabolic balance and preventing the progression of age-associated metabolic diseases. By synthesizing current research and highlighting potential clinical applications, this review provides a comprehensive framework for understanding the toxic legacy of cellular senescence and SASP in the metabolic arena, and it underscores the importance of targeting these pathways to mitigate chronic inflammation and metabolic dysfunction.

Abstract: Efficient delivery of biological material to the central nervous system (CNS) remains a key limitation of conventional gene therapies. Recently, we developed a novel strategy based on a secretable and cell-penetrating TATk-CDKL5 fused protein which enhances the brain biodistribution and the therapeutic efficiency of the gene therapy approach in a mouse model of CDKL5 Deficiency Disorder (CDD). Here, to compare the efficacy of the TATk-CDKL5 gene therapy with a conventional approach in correcting the CDD pathological phenotype, we employed cortical organoids generated from CDD patient-derived iPSCs as a human model of CDD. We found greater therapeutic efficacy of the recombinant TATk-CDKL5 protein compared to the CDKL5 protein alone in improving or ameliorating defects caused by the absence of CDKL5, such as abnormal hyperexcitability evaluated with microelectrode arrays (MEA). Interestingly, CDD cortical organoids exhibited reduced cell proliferation and increased neuronal cell death compared to control cortical organoids; defects that were only restored by the expression of the recombinant TATk-CDKL5 protein. These findings suggest the superior efficiency of a gene therapy based on a cross-correction approach for treating CDD.

Abstract: Metagenomic investigation of gut microbiome is a comprehensive and rapid technique for analysis and diagnosis of several diseases. Gut microbiome is a intricate ecosystem, structured by the interaction of various microbes and the metabolites produced by them, which helps in emerging and sustaining immunity and homeostasis. A healthy gut microbiome is driven by different factors such as nutrition, lifestyle etc. The current study examines the association of diet on gut microbiome dysbiosis and their role in disease conditions. Gut microbiome data collected from 73 patients, tested at BioAro Inc. lab, using shotgun metagenomics through next generation sequencing, analyzed and compared with data from 20 healthy subjects from HMP database. An in-house bioinformatics pipeline (PanOmiQ) was utilized for secondary and tertiary analysis was accomplished using R software. Results showed a higher number of opportunistic pathogen microorganisms in gut microbiome of subjects on a meat-based diet, as compared to a plant-based diet. These opportunistic pathogens included Ruminococcus torques (>3.34%), Ruminococcus gnavus (>2.22%) and Clostridium symbiosum (>1.87%). The study also found a higher relative abundance of these pathogens in cancer patients, as compared to healthy subjects. We also observed a highly significant (p< 0.0001) correlation of high meat-based diet with obesity in comparison to the subjects on a predominantly plant-based diet and the classified healthy subjects. Our findings suggest that patients following a plant-based diet have a lower relative abundance of pathogens, associated with cancer and or obesity. These findings provide critical insight into how we can use shotgun metagenomics to study composition and diversity of gut microbiome, how the diet affects gut microbiome and play an important role in metabolic and terminal diseases. This is the first report on investigating gut microbiota using shotgun metagenomics, correlating with different diseases and diet followed, which might impact the presence of opportunistic pathogens or keystones species. Additionally, it can provide valuable visions to physicians and dietetic practitioners for providing personalized treatment or to customize the diet plan.

Abstract: This study aimed to evaluate the effects of different storage conditions on seed viability, vigor, and agronomic performance in six forage pea (Pisum sativum L. var. arvense) cultivars: Uysal, Özkaynak, Kurtbey, Ürünlü, Taşkent, and Nany. The research was conducted under Manisa (Türkiye) field conditions during the 2021–2022 growing season, with supporting laboratory tests performed in Ankara. Seeds were evaluated before and after a three-month storage period under two conditions: room temperature and cold storage (5 °C, 60% RH). Laboratory analyses included germination percentage, germination speed, electrical conductivity (EC), and field emergence tests. Results revealed that cold storage significantly preserved seed vigor and viability, as indicated by lower EC values, higher germination and field emergence rates. Among cultivars, ‘Taşkent’ and ‘Nany’ demonstrated superior physiological seed quality, while ‘Uysal’ was more sensitive to adverse storage conditions. In field trials, cold-stored seeds produced taller plants, earlier flowering, and higher green and dry forage yields compared to room-stored seeds. The cultivar ‘Ürünlü’ stood out with the highest average forage yield. These findings underline the importance of genotype-specific responses and proper seed storage practices to maintain seed quality and optimize forage productivity in cool-season legumes.

Abstract: Digital twin technology is reshaping modern agriculture. Digital twins are the virtual replicas of real-world farming systems, which are continuously updated with real-time data, and are revolutionizing the monitoring, simulation, and optimization of agricultural processes. The literature on agricultural digital twins is multidisciplinary, growing rapidly, and often fragmented across disciplines, which lacks well-curated documentation. A bibliometric analysis includes thematic content analysis and science mapping, which provides research trends, gaps, thematic landscape, and key contributors in this continuously evolving and emerging field. Therefore, in this study, we conducted a bibliometric review that included collecting bibliometric data via keyword search strategies on popular scientific databases. The data was further screened, processed, analyzed, and visualized using bibliometric tools to map research trends, landscapes, collaborations, and themes. Key findings show that publications have grown exponentially since 2018, with an annual growth rate of 27.2%. The major contributing countries were China, the USA, the Netherlands, Germany, and India. We observed a collaboration network with distinct geographic clusters, with strong intra-European ties and more localized efforts in China and the USA. The analysis identified seven major research theme clusters revolving around precision farming, Internet of Things integration, artificial intelligence, cyber-physical systems, controlled-environment agriculture, sustainability, and food system applications. We observed that core technologies, such as sensors, artificial intelligence, and data analytics, have been extensively explored, while identifying gaps in research areas. The emerging interests include climate resilience, renewable-energy integration, and supply-chain optimization. The observed transition from task-specific tools to integrated, system-level approaches underline the growing need for adaptive, data-driven decision support. By outlining research trends and identifying strategic research gaps, this review offers insights into leveraging digital twins to improve productivity, sustainability, and resilience in global agriculture.

Abstract: Phase II oncology trials often rely on single-arm designs to test $H_0: \pi = \pi_0$ versus $H_a: \pi > \pi_0$, especially when randomized trials are infeasible due to cost or disease rarity. Traditional approaches like the exact binomial test and Simon’s two-stage design tend to be conservative, with actual Type I error rates falling below the nominal $\alpha$ due to discreteness of the underlying binomial processes. We propose a convolution-based method that combines the binomial distribution with a simulated normal variable to construct an unbiased estimator of $\pi$ and ensure precise Type I error control. We derive its theoretical properties and compare its performance to exact tests in both one-stage and two-stage settings. The approach yields more efficient designs with reduced sample sizes while maintaining error rate constraints. A new two-stage design with interim futility analysis is introduced and compared to Simon’s design. Real-world examples show the method’s potential to reduce trial cost and duration. This work offers a flexible, efficient alternative for early-phase oncology trial design.

Abstract: Animals are used in behavioural and biological research in special and significant ways. Many medical advancements that improve human life are based on laboratory animal research studies. Scientists carefully and thoughtfully select and justify the specific animal models used in their research, adhering to current legal requirements, the principles of the 3 R´s (reduction, reuse, and refinement), and ensuring that animals are used only when no other research solution is feasible or available. The laboratory animals most often used in biomedical research so far have been rodents (mice, rats, and guinea pigs), but in the current development of research, researchers have turned their attention to alternatives such as zebra fish and the Xenopus (clawed frog), although anatomically and physiologically different from humans, following the sequencing of their genomes, it was demonstrated that the main genes involved in certain pathologies in humans are similar to those in these animal models.

Abstract: Epithelial-mesenchymal transition (EMT) is prevalent in human cancer, and facilitates tumor metastasis and therapy resistance by enhancing cancer cell motility, invasiveness, survival, and immune evasion. However, the molecular mechanisms underlying the cellular changes during EMT remain largely elusive, making it challenging to simultaneously target these diverse malignant phenotypes. Here, we showed that the EMT-inducing ZEB transcription factors directly repressed WWC1 (also known as KIBRA), a key upstream activating component of the Hippo signaling pathway. The EMT program thus inherently downregulated WWC1, leading to impaired Hippo signaling and constitutive activation of the downstream effector and transcriptional coactivator YAP. The YAP-dependent transcriptional program promotes manifold cellular phenotypes that resemble those induced during EMT. Indeed, pharmacological inhibition of YAP suppressed EMT-stimulated cell migration and invasion, apoptosis resistance, and cell size growth, identifying active YAP as a common essential mediator of multiple EMT-associated phenotypes. Moreover, YAP activation directly induced transcription of B7 family immune checkpoint proteins VSIR (VISTA) and PD-L2, and rendered cancer cells resistant to effector CD8 T cells. Collectively, the results suggest that EMT intrinsically activates YAP by repressing WWC1, providing a non-genetic mechanism for pervasive YAP activation in cancer. Activated YAP in turn critically contributes to diverse EMT-enhanced malignant phenotypes and immune evasion. Therefore, pharmacological targeting of YAP may suppress various EMT-associated malignant properties and improve the efficacy of anti-PD-1 immunotherapy, offering a promising therapeutic strategy against cancer cells exhibiting EMT characteristics.

Abstract: This study examines the effect of an emulsion gel (EG) and a fat bulking agent (BA), both formulated with pork lard (PL) and an alginate-based gelling system, as animal fat replacers in the reformulation of reduced-fat fresh pork sausages. Both fat analogues were characterized in terms of texture, color and in vitro gastrointestinal digestion (GID) before being used in the reformulation of four fresh pork sausages, without and with added silicon (Si) from diatomaceous earth powder: S/EG, S/EG-Si, S/BA and S/BA-Si. Reduced-fat sausages elaborated exclusively with pork backfat (PB), without and with Si, were used as controls (S/C and S/C-Si). Both EG and BA showed adequate physicochemical characteristics and slowed in vitro GID compared to PL and PB. Replacing 75% PB with EG or BA did not negatively impact the technological, nutritional or sensory properties of the reformulated pork sausages, which were kept for 14 days under refrigeration. Additionally, sausages containing EG or BA as fat substitutes presented lower lipid digestibility after in vitro digestion compared to the control samples. The addition of Si further limited fat digestion, as reflected by the lower release of free fatty acids after in vitro GID compared to products without added Si. This effect was more pronounced in EG-based formulations. Therefore, the use of EG as PB replacer together with the addition of Si could become a promising strategy for developing healthier meat products.

Abstract: The response of the hypothalamic-pituitary-thyroid (HPT) to energy demands is perturbed by previous chronic stress perceived during the neonatal or the adult periods, We examined sex-specific effects of chronic variable stress (CVS) during adolescence on the responses of these axes and target peripheral tissues to volun-tary wheel-running (Ex) in adult rats. Two weeks of Ex stimulated mediobasal hypothalamus (MBH)-Pomc expression in both sexes, but this response was blunted by CVS. CVS altered basal HPA activity only of adult males increasing paraventricular nucleus (PVN) Gr and arcuate-Npy expression, and serum Cort levels. Ex reduced serum Cort concentration in controls. CVS decreased MBH-Dio2 and PVN-Trh expression, raising total and free T3 levels in females. In males, CVS reduced MBH-Dio2, -Trhde, and PVN-Trh expression, impairing exercise-induced expression and reducing serum T3/T4 ratio. The exer-cise-induced gene-expression of Dio2 and Pgc1a in skeletal muscle, of Adrb3, Dio2, Pparg, Hsl in inguinal and gonadal white-adipose tissues, and of Adrb3 and Ucp1 brown adipose tissue was blunted by CVS in both sexes except Hsl in in-guinal of both and BAT-Dio2 in brown adipose tissue of females that were not affected by stress. These results support that adolescent stress impacts adult met-abolic and neuroendocrine responses to exercise in a sex-specific manner.

Abstract: Nuclear receptors (NRs) are ligand-activated transcription factors that mediate diverse cellular processes, including signalling, survival, proliferation, immune response and metabolism, through both genomic and non-genomic mechanisms in response to hor-mones and metabolic ligands. Given their central role in inter-organ, tissue, and cellular communication, NRs are critical for maintaining homeostasis and have become a major focus in biomedical research and drug discovery due to their association with numerous diseases. Among NRs, the NR4A subfamily (NR4A1/Nur77, NR4A2/Nurr1, and NR4A3/Nor1) re-sponds to various stimuli—such as insulin, growth factors, inflammatory cytokines, and β-adrenergic signals—though their endogenous ligands remain unidentified. Their ex-pression is tissue-dependent, particularly in energy-demanding tissues, where they mod-ulate leukocyte function and promote an anti-inflammatory profile. Like other NRs, NR4As regulate acute and chronic inflammation by suppressing pro-inflammatory tran-scription factors (e.g., NF-κB) or enhancing their inhibitors, thereby polarising macro-phages toward an anti-inflammatory phenotype. This review summarises current knowledge on the role of NR4A receptors in immune re-sponses. Given their well-documented involvement in autoimmune diseases, inflammato-ry conditions, and cancer, elucidating their contributions to neuro-immune-endocrine crosstalk may uncover their therapeutic potential for immunopathological disorders.