One-year predictors of PTSD symptoms, anxiety, and depression in SARS-CoV-2 survivors: psychological flexibility and major life events as main predictive factors.

Introduction: The COVID-19 pandemic held considerable health-related outcomes worldwide, including mental health challenges, with elevated risk of psychiatric sequelae. Methods: This study aimed to test the longitudinal (1 year) predictive role of psychosocial factors on post-traumatic stress disorder (PTSD), anxiety, and depressive symptoms in SARS-CoV-2 survivors (N = 209 at T1; N = 61; attrition rate 70.83%), through Pearson's correlation analyses and longitudinal multiple regression analyses. Participants (age M = 35.4, SD = 10.1) completed online self-report questionnaires of psychosocial variables, PTSD, anxiety, and depression. Results: Depression and anxiety symptoms were increased, and 42% of survivors presented clinically meaningful PTSD symptoms. PTSD symptoms were longitudinally predicted by having children (ß = 0.32, p < 0.01), number of recent major life events (ß = 0.34, p < 0.01), and psychological flexibility (ß = -0.36, p < 0.01). Number of major life events (ß = 0.29, p < 0.05) and psychological flexibility (ß = -0.29, p < 0.05) predicted anxiety. Number of recent major life events (ß = 0.32, p < 0.01) was the sole predictor of depressive symptoms. Discussion: Psychosocial variables contribute to the long-term harmful effects of the COVID-19 pandemic on psychopathological symptoms. These results suggest that, during the pandemic, mental health was impacted by both socio-contextual factors and individual self-regulatory skills, namely the ability to respond flexibily to contextual cues and guide behavior according to the direct experience. Specifically, results point out the importance of societal incentives to reduce parental burden and socioeconomic losses, as well as to promote adaptive psychological skills such as psychological flexibility.

eLIFEwithIBD: study protocol for a randomized controlled trial of an online acceptance and commitment therapy and compassion-based intervention in inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) entails physical, psychological, and social burden and holds a significant impact on quality of life. Experiential avoidance, cognitive fusion, shame, and self-criticism have been identified as possible therapeutic targets for improving mental health in people with IBD. Traditional face-to-face psychological therapy continues to provide obstacles for patients seeking assistance. Online psychological therapies centered on acceptance, mindfulness, and compassion have been shown to improve psychological distress in other populations. Objective: This paper presents the study protocol of a two-arm Randomized Controlled Trial (RCT) of an ACT and compassion-based, online intervention - eLIFEwithIBD - on the improvement of psychological distress, quality of life, work and social functioning, IBD symptom perception, illness-related shame, psychological flexibility, and self-compassion. Methods: The eLIFEwithIBD intervention is an adaptation of the LIFEwithIBD programme (delivered through an in-person group format) and entails an ACT, mindfulness, and compassion-based intervention designed to be delivered as an e-health tool for people with IBD. This protocol outlines the structure and contents of the eLIFEwithIBD intervention. Participants were recruited by an advertisement on the social media platforms of Portuguese Associations for IBD in January 2022. A psychologist conducted a brief interview with 80 patients who were interested in participating. Fifty-five participants were selected and randomly assigned to one of two conditions [experimental group (eLIFEwithIBD + medical TAU; n = 37) or control group (medical TAU; n = 18)]. Outcome measurement took place at baseline, post-intervention, and 4-month follow-up. All analyses are planned as intent-to-treat (ITT). Results: The eLIFEwithIBD intervention is expected to empower people with IBD by fostering psychological strategies that promote illness adjustment and well-being and prevent subsequent distress. The eLIFEwithIBD aims to gain a novel and better understanding of the role of online contextual behavioral interventions on improving the quality of life and mental health of people with IBD. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05405855, NCT05405855.

Advances in exosomes utilization for clinical applications in cancer.

Exosomes are regarded as having transformative potential for clinical applications. Exosome-based liquid biopsies offer a noninvasive method for early cancer detection and real-time disease monitoring. Clinical trials are underway to validate the efficacy of exosomal biomarkers for enhancing diagnostic accuracy and predicting treatment responses. Additionally, engineered exosomes are being developed as targeted drug delivery systems that can navigate the bloodstream to deliver therapeutic agents to tumor sites, thus enhancing treatment efficacy while minimizing systemic toxicity. Exosomes also exhibit immunomodulatory properties, which are being harnessed to boost antitumor immune responses. In this review, we detail the latest advances in clinical trials and research studies, underscoring the potential of exosomes to revolutionize cancer care.

Substrate-dependent oxidative inactivation of a W-dependent formate dehydrogenase involving selenocysteine displacement.

Metal-dependent formate dehydrogenases are very promising targets for enzyme optimization and design of bio-inspired catalysts for CO2 reduction, towards innovative strategies for climate change mitigation. For effective application of these enzymes, the catalytic mechanism must be better understood, and the molecular determinants clarified. Despite numerous studies, several doubts persist, namely regarding the role played by the possible dissociation of the SeCys ligand from the Mo/W active site. Additionally, the oxygen sensitivity of these enzymes must also be understood as it poses an important obstacle for biotechnological applications. This work presents a combined biochemical, spectroscopic, and structural characterization of Desulfovibrio vulgaris FdhAB (DvFdhAB) when exposed to oxygen in the presence of a substrate (formate or CO2). This study reveals that O2 inactivation is promoted by the presence of either substrate and involves forming a different species in the active site, captured in the crystal structures, where the SeCys ligand is displaced from tungsten coordination and replaced by a dioxygen or peroxide molecule. This form was reproducibly obtained and supports the conclusion that, although W-DvFdhAB can catalyse the oxidation of formate in the presence of oxygen for some minutes, it gets irreversibly inactivated after prolonged O2 exposure in the presence of either substrate.

Hybrid brain tumor classification of histopathology hyperspectral images by linear unmixing and an ensemble of deep neural networks.

Hyperspectral imaging has demonstrated its potential to provide correlated spatial and spectral information of a sample by a non-contact and non-invasive technology. In the medical field, especially in histopathology, HSI has been applied for the classification and identification of diseased tissue and for the characterization of its morphological properties. In this work, we propose a hybrid scheme to classify non-tumor and tumor histological brain samples by hyperspectral imaging. The proposed approach is based on the identification of characteristic components in a hyperspectral image by linear unmixing, as a features engineering step, and the subsequent classification by a deep learning approach. For this last step, an ensemble of deep neural networks is evaluated by a cross-validation scheme on an augmented dataset and a transfer learning scheme. The proposed method can classify histological brain samples with an average accuracy of 88%, and reduced variability, computational cost, and inference times, which presents an advantage over methods in the state-of-the-art. Hence, the work demonstrates the potential of hybrid classification methodologies to achieve robust and reliable results by combining linear unmixing for features extraction and deep learning for classification.

Human Chorionic Membrane-derived Tunable Hydrogels for Vascular Tissue Engineering Strategies.

One of the foremost targets in the advancement of biomaterials to engineer vascularized tissues is not only to replicate the composition of the intended tissue but also to create thicker structures incorporating a vascular network for adequate nutrients and oxygen supply. For the first time, to the best of current knowledge, a clinically relevant biomaterial is developed, demonstrating that hydrogels made from the human decellularized extracellular matrix can exhibit robust mechanical properties (in the kPa range) and angiogenic capabilities simultaneously. These properties enable the culture and organization of human umbilical vein endothelial cells into tubular structures, maintaining their integrity for 14 days in vitro without the need for additional polymers or angiogenesis-related factors. This is achieved by repurposing the placenta chorionic membrane (CM), a medical waste with an exceptional biochemical composition, into a valuable resource for bioengineering purposes. After decellularization, the CM underwent chemical modification with methacryloyl groups, giving rise to methacrylated CM (CMMA). CMMA preserved key proteins, as well as glycosaminoglycans. The resulting hydrogels rapidly photopolymerize and have enhanced strength and customizable mechanical properties. Furthermore, they demonstrate angio-vasculogenic competence in vitro and in vivo, holding significant promise as a humanized platform for the engineering of vascularized tissues.

Amniotic Membrane-Derived Multichannel Hydrogels for Neural Tissue Repair.

In the pursuit of advancing neural tissue regeneration, biomaterial scaffolds have emerged as promising candidates, offering potential solutions for nerve disruptions. Among these scaffolds, multichannel hydrogels, characterized by meticulously designed micrometer-scale channels, stand out as instrumental tools for guiding axonal growth and facilitating cellular interactions. This study explores the innovative application of human amniotic membranes modified with methacryloyl domains (AMMA) in neural stem cell (NSC) culture. AMMA hydrogels, possessing a tailored softness resembling the physiological environment, are prepared in the format of multichannel scaffolds to simulate native-like microarchitecture of nerve tracts. Preliminary experiments on AMMA hydrogel films showcase their potential for neural applications, demonstrating robust adhesion, proliferation, and differentiation of NSCs without the need for additional coatings. Transitioning into the 3D realm, the multichannel architecture fosters intricate neuronal networks guiding neurite extension longitudinally. Furthermore, the presence of synaptic vesicles within the cellular arrays suggests the establishment of functional synaptic connections, underscoring the physiological relevance of the developed neuronal networks. This work contributes to the ongoing efforts to find ethical, clinically translatable, and functionally relevant approaches for regenerative neuroscience.

Comparative analysis of aligned and random amniotic membrane-derived cryogels for neural tissue repair.

The ordered arrangement of cells and extracellular matrix facilitates the seamless transmission of electrical signals along axons in the spinal cord and peripheral nerves. Therefore, restoring tissue geometry is crucial for neural regeneration. This study presents a novel method using proteins derived from the human amniotic membrane, which is modified with photoresponsive groups, to produce cryogels with aligned porosity. Freeze-casting was used to produce cryogels with longitudinally aligned pores, while cryogels with randomly distributed porosity were used as the control. The cryogels exhibited remarkable injectability and shape-recovery properties, essential for minimally invasive applications. Different tendencies in proliferation and differentiation were evident between aligned and random cryogels, underscoring the significance of the scaffold's microstructure in directing the behaviour of neural stem cells (NSC). Remarkably, aligned cryogels facilitated extensive cellular infiltration and migration, contrasting with NSC cultured on isotropic cryogels, which predominantly remained on the scaffold's surface throughout the proliferation experiment. Significantly, the proliferation assay demonstrated that on day 7, the aligned cryogels contained eight times more cells compared to the random cryogels. Consistent with the proliferation experiments, NSC exhibited the ability to differentiate into neurons within the aligned scaffolds and extend neurites longitudinally. In addition, differentiation assays showed a four-fold increase in the expression of neural markers in the cross-sections of the aligned cryogels. Conversely, the random cryogels exhibited minimal presence of cell bodies and extensions. The presence of synaptic vesicles on the anisotropic cryogels indicates the formation of functional synaptic connections, emphasizing the importance of the scaffold's microstructure in guiding neuronal reconnection.

Enhanced chondrogenic potential in GelMA-based 3D cartilage model via Wnt3a surface immobilization.

Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture systems lack the complexity of native cartilage, leading to the development of 3D regenerative cartilage models. In this study, we developed a 3D model using Gelatin Methacryloyl (GelMA)-based hydrogels seeded with Y201 cells, a bone marrow mesenchymal stem cell line. The model investigated chondrogenic differentiation potential in response to Wnt3a stimulation within the GelMA scaffold and validated using known chondrogenic agonists. Y201 cells demonstrated suitability for the model, with increased proteoglycan content and upregulated chondrogenic marker expression under chondrogenic conditions. Wnt3a enhanced cell proliferation, indicating activation of the Wnt/ß-catenin pathway, which plays a role in cartilage development. GelMA hydrogels provided an optimal scaffold, supporting cell viability and proliferation. The 3D model exhibited consistent responses to chondrogenic agonists, with TGF-ß3 enhancing cartilage-specific extracellular matrix (ECM) production and chondrogenic differentiation. The combination of Wnt3a and TGF-ß3 showed synergistic effects, promoting chondrogenic differentiation and ECM production. This study presents a 3D regenerative cartilage model with potential for investigating cartilage biology, disease mechanisms, and drug screening. The model provides insights into complex cartilage regeneration mechanisms and offers a platform for developing therapeutic approaches for cartilage repair and osteoarthritis treatment.

Non-conductive silicon-containing materials improve methane production by pure cultures of methanogens.

Conductive materials (CM) enhance methanogenesis, but there is no clear correlation between conductivity and faster methane production (MP) rates. We investigated if MP by pure cultures of methanogens (Methanobacterium formicicum, Methanospirillum hungatei, Methanothrix harundinacea and Methanosarcina barkeri) is affected by CM (activated carbon (AC), magnetite), and other sustainable alternatives (sand and glass beads, without conductivity, and zeolites (Zeo)). The significant impact of the materials was on M. formicicum as MP was significantly accelerated by non-CM (e.g., sand reduced the lag phase (LP) duration by 48 %), Zeo and AC (LP reduction in 71% and 75 %, respectively). Conductivity was not correlated with LP reduction. Instead, silicon content in the materials was inversely correlated with the time required for complete MP, and silicon per se stimulated M. formicicum's activity. These findings highlight the potential of using non-CM silicon-containing materials in anaerobic digesters to accelerate methanogenesis.

Immunometabolic Blood Biomarkers of Developmental Trajectories of Depressive Symptoms: Findings From the ALSPAC Birth Cohort.

Studies of longitudinal trends of depressive symptoms in young people could provide insight into aetiologic mechanism, heterogeneity and origin of common cardiometabolic comorbidities for depression. Depression is associated with immunological and metabolic alterations, but immunometabolic characteristics of developmental trajectories of depressive symptoms remain unclear. Using depressive symptoms scores measured on 10 occasions between ages 10 and 25 years in the Avon Longitudinal Study of Parents and Children (n=7302), we identified four distinct trajectories: low-stable (70% of the sample), adolescent-limited (13%), adulthood-onset (10%) and adolescent-persistent (7%). We examined associations of these trajectories with: i) anthropometric, cardiometabolic and psychiatric phenotypes using multivariable regression (n=1709-3410); ii) 67 blood immunological proteins and 57 metabolomic features using empirical Bayes moderated linear models (n=2059 and n=2240 respectively); and iii) 28 blood cell counts and biochemical measures using multivariable regression (n=2256). Relative to the low-stable group, risk of depression and anxiety in adulthood was higher for all other groups, especially in the adolescent-persistent (ORdepression=22.80, 95% CI 15.25-34.37; ORGAD=19.32, 95% CI 12.86-29.22) and adulthood-onset (ORdepression=7.68, 95% CI 5.31-11.17; ORGAD=5.39, 95% CI 3.65-7.94) groups. The three depression-related trajectories vary in their immunometabolic profile, with evidence of little or no alterations in the adolescent-limited group. The adulthood-onset group shows widespread classical immunometabolic changes (e.g., increased immune cell counts and insulin resistance), while the adolescent-persistent group is characterised by higher BMI both in childhood and adulthood with few other immunometabolic changes. These findings point to distinct mechanisms and intervention opportunities for adverse cardiometabolic profile in different groups of young people with depression.

Role of sulfidogenic members of the gut microbiota in human disease.

The human gut flora comprises a dynamic network of bacterial species that coexist in a finely tuned equilibrium. The interaction with intestinal bacteria profoundly influences the host's development, metabolism, immunity, and overall health. Furthermore, dysbiosis, a disruption of the gut microbiota, can induce a variety of diseases, not exclusively associated with the intestinal tract. The increased consumption of animal protein, high-fat and high-sugar diets in Western countries has been implicated in the rise of chronic and inflammatory illnesses associated with dysbiosis. In particular, this diet leads to the overgrowth of sulfide-producing bacteria, known as sulfidogenic bacteria, which has been linked to inflammatory bowel diseases and colorectal cancer, among other disorders. Sulfidogenic bacteria include sulfate-reducing bacteria (Desulfovibrio spp.) and Bilophila wadsworthia among others, which convert organic and inorganic sulfur compounds to sulfide through the dissimilatory sulfite reduction pathway. At high concentrations, sulfide is cytotoxic and disrupts the integrity of the intestinal epithelium and mucus barrier, triggering inflammation. Besides producing sulfide, B. wadsworthia has revealed significant pathogenic potential, demonstrated in the ability to cause infection, adhere to intestinal cells, promote inflammation, and compromise the integrity of the colonic mucus layer. This review delves into the mechanisms by which taurine and sulfide-driven gut dysbiosis contribute to the pathogenesis of sulfidogenic bacteria, and discusses the role of these gut microbes, particularly B. wadsworthia, in human diseases.

Exploring the potential of human intestinal organoids: Applications, challenges, and future directions.

The complex and dynamic environment of the gastrointestinal tract shapes one of the fastest renewing tissues in the human body, the intestinal epithelium. Considering the lack of human preclinical studies, reliable models that mimic the intestinal environment are increasingly explored. Patient-derived intestinal organoids are powerful tools that recapitulate in vitro many pathophysiological features of the human intestine. In this review, the possible applications of human intestinal organoids in different research fields are highlighted. From physiologically relevant to intestinal disease modeling, regenerative medicine, and toxicology studies, the potential of intestinal organoids will be here presented and discussed. Despite the remarkable opportunities offered, limitations related to ethical concerns, tissue collection, reproducibility, and methodologies may hinder the full exploitation of this cell-based model into high throughput studies and clinical practice. Currently, distinct approaches can be used to overcome the numerous challenges found along the way and to allow the full implementation of this ground-breaking technology.

Structural and biochemical characterization of the M405S variant of Desulfovibrio vulgaris formate dehydrogenase.

Molybdenum- or tungsten-dependent formate dehydrogenases have emerged as significant catalysts for the chemical reduction of CO2 to formate, with biotechnological applications envisaged in climate-change mitigation. The role of Met405 in the active site of Desulfovibrio vulgaris formate dehydrogenase AB (DvFdhAB) has remained elusive. However, its proximity to the metal site and the conformational change that it undergoes between the resting and active forms suggests a functional role. In this work, the M405S variant was engineered, which allowed the active-site geometry in the absence of methionine Sδ interactions with the metal site to be revealed and the role of Met405 in catalysis to be probed. This variant displayed reduced activity in both formate oxidation and CO2 reduction, together with an increased sensitivity to oxygen inactivation.

Randomized controlled trial of an Acceptance and Commitment Therapy and compassion-based group intervention for persons with inflammatory bowel disease: the LIFEwithIBD intervention.

Objectives: This study tested the acceptability and efficacy of an Acceptance and Commitment Therapy and compassion-based intervention (LIFEwithIBD) in people with IBD through a two-arm RCT. Methods: Participants were recruited at the Gastroenterology Department of the Coimbra University Hospital between June and September 2019. Of the 355 patients screened, those who accepted to participate were randomly assigned to one of two conditions: experimental group (LIFEwithIBD; n = 25) or control group (waitlist; n = 29). Participants completed self-report measures at baseline (T0), post-intervention (T1), and 3-month (T2) and 12-month (T3) follow-ups. Intervention acceptability was assessed. Efficacy was examined using intent-to-treat ANCOVA at post-intervention after adjusting for baseline values of depressive, anxiety, and stress symptoms (primary outcomes). Linear mixed models for all longitudinal outcomes were also analysed. Inflammatory and disease biomarkers were determined at T0 and T3. Results: Acceptability results revealed a high level of satisfaction and perceived usefulness regarding the intervention. Both groups experienced a significant decrease in stress symptoms and IBD symptom perception at T1. No significant differences were observed at follow-up for the primary outcomes. The experimental group reported significantly lower Crohn's disease Symptom severity at T2 than the control group. Post-hoc analyses designed to mitigate floor effects revealed substantial treatment effects for the experimental group regarding anxiety symptoms. No significant differences were observed in clinical biomarkers from T0 to T3. Conclusion: The LIFEwithIBD intervention shows promising, although preliminary, benefits for managing disease activity and reducing anxiety symptoms in IBD patients with high severity of psychological distress.Clinical trial registration: https://www.clinicaltrials.gov/ct2/show/NCT03840707, identifier NCT03840707.

Influence of taurine on the zootechnical performance and health parameters of juvenile Nile tilapia in a recirculating aquaculture system.

Taurine is considered a conditionally essential amino acid for fish, so its supplementation may improve feed conversion. This study evaluated the supplementation of taurine on growth performance, hematological and immunological parameters, production costs, and survival of Nile tilapia (Oreochromis niloticus) juveniles raised in a recirculating aquaculture system (RAS). A control diet was formulated with 360 g kg-1 of crude protein without fish meal and without taurine supplementation (Control). From the control diet, another diet supplemented with 9.7 g of taurine per kg of feed (Taurine) was produced. Fish fed diet supplemented with taurine had lower daily average weight gain and final average weight compared to the control diet (p < 0.05). It was observed that taurine had no influence on condition factor, survival, or hemato-immunological parameters of Nile tilapia juveniles, but there was a higher mean corpuscular volume and greater nitrogen retention in fish from the control group (p < 0.05). It is concluded that Nile tilapia juveniles do not benefit from taurine supplementation in RAS, even when fed diet containing plant-based protein sources.

Energy flux couples sulfur isotope fractionation to proteomic and metabolite profiles in Desulfovibrio vulgaris.

Microbial sulfate reduction is central to the global carbon cycle and the redox evolution of Earth's surface. Tracking the activity of sulfate reducing microorganisms over space and time relies on a nuanced understanding of stable sulfur isotope fractionation in the context of the biochemical machinery of the metabolism. Here, we link the magnitude of stable sulfur isotopic fractionation to proteomic and metabolite profiles under different cellular energetic regimes. When energy availability is limited, cell-specific sulfate respiration rates and net sulfur isotope fractionation inversely covary. Beyond net S isotope fractionation values, we also quantified shifts in protein expression, abundances and isotopic composition of intracellular S metabolites, and lipid structures and lipid/water H isotope fractionation values. These coupled approaches reveal which protein abundances shift directly as a function of energy flux, those that vary minimally, and those that may vary independent of energy flux and likely do not contribute to shifts in S-isotope fractionation. By coupling the bulk S-isotope observations with quantitative proteomics, we provide novel constraints for metabolic isotope models. Together, these results lay the foundation for more predictive metabolic fractionation models, alongside interpretations of environmental sulfur and sulfate reducer lipid-H isotope data.

Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.