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Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively. Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1G93A mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability. Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels. Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.

Abstract Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer’s disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, “loss-of-function” profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte “loss-of-function” profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.

Considerable evidence has accumulated regarding the molecular relationship between gut microbiota (GM) composition and the onset (clinical presentation and prognosis of ulcerative colitis (UC)). In addition, it is well documented that short-chain fatty acid (SCFA)-producing bacteria may play a fundamental role in maintaining an anti-inflammatory intestinal homeostasis, but sulfate- and sulfite reducing bacteria may be responsible for the production of toxic metabolites, such as hydrogen sulfide and acetate. Hence, the present study aimed to assess the GM composition – focusing on sulfate-reducing bacteria (SRB) – in patients with severe, severe-active and moderate UC. Each one of the six enrolled patients provided two stool samples in the following way: one sample was cultivated in a modified SRB-medium before 16S rRNA sequencing and the other was not cultivated. Comparative phylogenetic analysis was conducted on each sample. Percentage of detected gut microbial genera showed considerable variation based on the patients’ disease severity and cultivation in the SRB medium. In detail, samples without cultivation from patients with moderate UC showed a high abundance of the genera Bacteroides, Bifidobacterium and Ruminococcus, but after SRB cultivation, the dominant genera were Bacteroides, Klebsiella and Bilophila. On the other hand, before SRB cultivation, the main represented genera in patients with severe UC were Escherichia-Shigella, Proteus, Methanothermobacter and Methanobacterium. However, after incubation in the SRB medium Bacteroides, Proteus, Alistipes and Lachnoclostridium were predominant. Information regarding GM compositional changes in UC patients may aid the development of novel therapeutic strategies (e.g., probiotic preparations containing specific bacterial strains) to counteract the mechanisms of virulence of harmful bacteria and the subsequent inflammatory response that is closely related to the pathogenesis of inflammatory bowel diseases.

Achieving climate neutrality requires reducing energy consumption and CO2 emissions in the building sector, which has prompted increasing attention towards nearly zero energy, zero energy, and positive energy communities of buildings; there is a need to determine how individual buildings up to communities of buildings can become more energy efficient. This study addresses the scientific problem of optimizing energy efficiency strategies in building areas and identifies gaps in existing theories related to passive design strategies, active energy systems, and renewable energy integration. This study delineates boundaries at the building and community scales to examine the challenges of attaining energy efficiency goals and to emphasize the intricate processes of selecting, integrating, and optimizing energy systems in buildings. The four boundaries describe: (B1) energy flows through the building envelope; (B2) energy flows through heating, ventilation, air conditioning and energy systems; (B3) energy flows through individual buildings; (B4) energy flows through a community of buildings. Current theories often treat these elements in isolation, and significant gaps exist in interdisciplinary integration, scalable frameworks, and the consideration of behavioral and socioeconomic factors. Achieving nearly zero energy, zero energy, and positive energy communities requires seamless integration of renewable energy sources, energy storage systems, and energy management systems. The proposed boundaries B1–B4 can help not only in analyzing the various challenges for achieving high energy efficiency in building communities but also in defining and evaluating these communities and establishing fair methods for energy distribution within them. The results demonstrate that these boundaries provide a comprehensive framework for energy-efficient designs, constructions, and operational practices across multiple buildings, ensuring equitable energy distribution and optimized performance. In addition, the definition of boundaries as B1-B4 contributes to providing an interface for energy-efficient designs, constructions and operational practices across multiple buildings.

Abstract Background Emerging evidence suggests that breast microbiota dysbiosis contributes to cancer initiation, progression, prognosis and treatment efficacy. Anyway, available data are referred only to female patients, and studies on males are completely missing. Male breast cancer (MBC) is 70–100 times less frequent, but the mortality rate adjusted to incidence is higher in men than in females. Currently, MBC diagnostic approaches and treatments have generally been extrapolated from the clinical experience gained in women, while few studies focus on characterizing male cancer biology. Taking into account the rising importance of the oncobiome field and the need of MBC targeted studies, we explored the breast cancer oncobiome of male and female patients. Methods 16S rRNA gene sequencing was performed in 20 tumor and 20 non-pathological adjacent FFPE breast tissues from male and female patients. Results We documented, for the first time, the presence of a sexually dimorphic breast-associated microbiota, here defined as “breast microgenderome”. Moreover, the paired analysis of tumor and non-pathological adjacent tissues suggests the presence of a cancer-associated dysbiosis in male patients, with surrounding tissue conserving a healthier microbiome, whereas in female patients, the entire breast tissue is predisposed to cancer development. Finally, the phylum Tenericutes, especially the genera Mesoplasma and Mycobacterium, could to be involved in breast carcinogenesis, in both sexes, deserving further investigation, not only for its role in cancer development but even as potential prognostic biomarker. Conclusions Breast microbiota characterization can enhance the understanding of male breast cancer pathogenesis, being useful for detection of new prognostic biomarkers and development of innovative personalized therapies, remarking the relevant gender differences.

Introduction: Calcific aortic valve disease (CAVD) is the most common heart valve disorder, defined by a remodeling multistep process: namely, valve fibrosis with its area narrowing, impaired blood flow, and final calcification phase. Nowadays, the only treatment is the surgical valve replacement. As for other cardiovascular diseases, growing evidence suggest an active role of the immune system in the calcification process that could be modulated by the microbiota. To address this point, we aimed to investigate and characterize, for the first time, the presence of a valve microbiota and associated immune response in human CAVD. Method: Calcified aortic valve (CAV) samples from twenty patients (11 from Germany and 9 from Italy) with diagnosis of severe symptomatic CAVD were used to assess the presence of infiltrating T cells, by cloning approach, and to characterize the valve microbiota, by 16S rRNA gene sequencing (NGS). Results: We documented the presence of infiltrating T lymphocytes, especially the T helper subset, in CAV samples. Moreover, we found a tissue-associated microbiota in freshly collected CAV samples, which was significantly different in Italian and German patients, suggesting potential correlation with other cardiovascular risk factors. Conclusion: The presence of microbiota in inflamed CAV samples represents the right trigger point to explain the valve calcification process, encouraging further studies to explore the potential link between bacteria and adaptive immune response and to define the critical role of local microbiota-immunity axis on CAVD development.

Background: Approximately 95% of Colorectal cancers (CRC) consist of adenocarcinomas originating from colonic Adenomatous polyps (AP). Increasing importance in CRC occurrence and progression has been attributed to the gut microbiota; however, a huge proportion of microorganisms inhabit the human digestive system. So, to comprehensively study the microbial spatial variations and their role in CRC progression, from AP to the different CRC phases, a holistic vision is imperative, including the simultaneous evaluation of multiple niches from the gastrointestinal system. Through an integrated approach, we identified potential microbial and metabolic biomarkers, able to discriminate human CRC from AP and/or also the different Tumor node metastasis (TNM) staging. In addition, as the microbiota contributes to the production of essential metabolic products detectable in fecal samples, we analysed and compared metabolites obtained from CRC and AP patients by using a Nuclear magnetic resonance (NMR) approach. Methods: In this observational study, saliva, tissue and stool samples from 61 patients, have been collected, including 46 CRC and 15 AP patients, age and sex-matched, undergoing surgery in 2018 at the Careggi University Hospital (Florence, Italy). First, the microbiota in the three-district between CRC and AP patients has been characterized, as well as in different CRC TNM stages. Subsequently, proton NMR spectroscopy has been used in combination with multivariate and univariate statistical approaches, to define the fecal metabolic profile of a restricted group of CRC and AP patients. Results: CRC patients display a different profile of tissue and fecal microbiota with respect to AP patients. Significant differences have been observed in CRC tissue microbial clades, with a rise of the Fusobacterium genus. In addition, significant taxa increase at the genus level has been observed in stool samples of CRC patients. Furthermore, Fusobacterium found in intestinal tissue has been positively correlated with fecal Parvimonas, for the first time. Moreover, as predicted by metagenomics pathway analysis, a significant increase of lactate (p=0.037) has been observed in the CRC fecal metabolic profiles, and positively correlated with Bifidobacterium (p=0.036). Finally, minor bacterial differences in CRC patients at stage T2 (TNM classification) have been detected, with a raise of the Spirochaetota phylum in CRC samples, with a slight increase of the Alphaproteobacteria class in fecal samples. Conclusion: Our results suggest the importance of microbiota communities and oncometabolites in CRC development. Further studies on CRC/AP management with a focus on CRC assessment are needed to investigate novel microbial-related diagnostic tools aimed to improve therapeutic interventions.

Background and aimIn recent decades, obesity prevalence has reached epidemic proportions and considering the pivotal role of gut microbiota (GM) in the regulation of energy balance, alternative non-pharmacological approaches involving probiotics’ administration have been proposed. The aim of the present study was to evaluate the effect of Lactiplantibacillus plantarum IMC 510® supplementation on anthropometric and biochemical parameters, GM composition and functionality, and gastrointestinal and general symptoms of overweight/obese subjects.MethodsForty overweight/obese subjects were randomly assigned to daily consume the probiotic Lactiplantibacillus plantarum IMC 510® or placebo for 3 months. Before and after the administration period, anthropometric and biochemical parameters, self-administered questionnaires, and plasma and stool samples were obtained from each participant. The GM characterization was performed with 16S rRNA sequencing, while fecal short (SCFAs) and medium (MCFAs) chain fatty acids were analyzed with a gas chromatography–mass spectrometry protocol.ResultsCompared to placebo, probiotic supplementation determined a significant decrease in body weight, BMI, waist circumference, waist-to-height ratio, and blood glucose. Moreover, probiotic administration produced a significant decrease of the genera Hafnia-Obesumbacterium and Romboutsia and an increase of Succiniclasticum spp.; conversely, placebo administration resulted in the decrease of Actinomycetaceae and an increase of both Alloprevotella spp. and of the levels of pro-inflammatory hexanoic and heptanoic acids.ConclusionThanks to its effect in increasing some beneficial gut bacteria and lowering effects on waist circumference, fasting glucose levels and gastrointestinal symptoms of obese subjects, Lactiplantibacillus plantarum IMC 510® supplementation could represent a future and encouraging strategy for the prevention or treatment of obesity.

The composition of the gut microbiota (GM) undergoes significant changes during pregnancy, influenced by metabolic status, energy homeostasis, fat storage, and hormonal and immunological modifications. Moreover, dysbiosis during pregnancy has been associated with preterm birth, which is influenced by factors such as cervical shortening, infection, inflammation, and oxidative stress. However, dysbiosis also affects the levels of lipopolysaccharide-binding protein (LBP), short-chain fatty acids (SCFAs), and free fatty acids (FFA) in other tissues and the bloodstream. In this study, we investigated the plasmatic levels of some pro-inflammatory cytokines, such as matrix metalloproteinases-8 (MMP-8), interleukin-8 (IL-8), heat shock protein 70 (Hsp70), and microbial markers in pregnant women with a short cervix (≤25 mm) compared to those with normal cervical length (>25 mm). We examined the differences in the concentration of these markers between the two groups, also assessing the impact of gestational diabetes mellitus. Understanding the relationship between GM dysbiosis, inflammatory mediators, and cervical changes during pregnancy may contribute to the identification of potential biomarkers and therapeutic targets for the prevention and management of adverse pregnancy outcomes, including preterm birth.

IntroductionPotential celiac disease (pCD) is characterized by genetic predisposition, positive anti-endomysial and anti-tissue transglutaminase antibodies, but a normal or almost normal jejunal mucosa (e.g., minor histological abnormalities without villous atrophy). To gain further insights into basic mechanisms involved in the development of intestinal villous atrophy, we evaluated and compared the microbial, lipid, and immunological signatures of pCD and atrophic CD (aCD).Materials and methodsThis study included 17 aCD patients, 10 pCD patients, and 12 healthy controls (HC). Serum samples from all participants were collected to analyze free fatty acids (FFAs). Duodenal mucosa samples of aCD and pCD patients were taken to evaluate histology, tissue microbiota composition, and mucosal immune response.ResultsWe found no significant differences in the mucosa-associated microbiota composition of pCD and aCD patients. On the other hand, in pCD patients, the overall abundance of serum FFAs showed relevant and significant differences in comparison with aCD patients and HC. In detail, compared to HC, pCD patients displayed higher levels of propionic, butyric, valeric, 2-ethylhexanoic, tetradecanoic, hexadecanoic, and octadecanoic acids. Instead, aCD patients showed increased levels of propionic, isohexanoic, and 2-ethylhexanoic acids, and a lower abundance of isovaleric and 2-methylbutyricacids when compared to HC. In addition, compared to aCD patients, pCD patients showed a higher abundance of isobutyric and octadecanoic acid. Finally, the immunological analysis of duodenal biopsy revealed a lower percentage of CD4+ T lymphocytes in pCD infiltrate compared to that observed in aCD patients. The functional characterization of T cells documented a pro-inflammatory immune response in both aCD and pCD patients, but the pCD patients showed a higher percentage of Th0/Th17 and a lower percentage of Th1/Th17.ConclusionThe results of the present study show, for the first time, that the duodenal microbiota of patients with pCD does not differ substantially from that of aCD; however, serum FFAs and local T cells displayed a distinctive profile between pCD, aCD, and HC. In conclusion, our result may help to shed new light on the “gut microbiota-immunity axis,” lipid metabolites, and duodenal immune response in overt CD and pCD patients, opening new paradigms in understanding the pathogenesis behind CD progression.

Background and aimIn recent years, many studies have suggested that ancient wheat products might have beneficial effects on cardiometabolic risk profile, but little is known about their effect on gut microbiota (GM). The aim of the present study was to evaluate whether a replacement diet with pasta made from ancient wheat (AD) could influence the GM composition and its metabolites’ production compared to a replacement diet with pasta made from modern wheat (CD).MethodsA randomized, double-blinded crossover trial with two intervention phases was conducted on 20 clinically healthy adults (9 females; 11 males; mean age 43.1 ± 12.5 years). Study participants were assigned to consume pasta made using semi-whole flour from organic wheat that was either from ancient or modern control wheat for 8 weeks in a random order. An 8-week washout period was implemented between the interventions. Stool samples were collected from all subjects at the beginning and at the end of each intervention period. GM composition, and short- (SCFAs) and medium- chain fatty acids (MCFAs) production was evaluated.ResultsDietary interventions did not produce significant diversity in the GM composition at higher ranks (phylum, class, order and family), but only at genus level. In detail, the AD significantly (adj. p < 0.05) changed the abundance of Erysipelatoclostridium spp., Bacteroides_pectinophilus_group spp., CAG-873 spp., and Holdemanella spp. The CD significantly affected the abundance of Akkermansia spp., CAG-873 spp., Hungatella spp., Lachnospiraceae_UCG-008 spp., NK4A214_group spp., Frisingicoccus spp., Megasphaera spp., Synergistes spp., and Tyzzerella spp. Regarding the production of SCFAs and MCFAs, AD resulted in a significant increase of fecal acetic (+0.7%), isobutyric (+30.1%), 2-methylbutyric (+64.2%), and isovaleric (+22.5%) acids. On the other hand, CD resulted in increased levels of isobutyric (+71.4%), 2-methylbutyric (+116.2%), isovaleric (+99%), and valeric (+21.4%) acids, and a reduction of butyric (-31.6%) and hexanoic (-66.4%) acids.ConclusionA short-term replacement diet with both ancient and modern wheat pasta determined significant changes in GM composition at the genus level but notably the AD resulted in a greater beneficial impact on anti-inflammatory SCFAs.

Background and aimsCrohn’s disease (CD) pathogenesis is still unclear. Remodeling in mucosal microbiota and systemic immunoregulation may represent an important component in tissue injury. Here, we aim to characterize the ileal microbiota in both pathological and healthy settings and to evaluate the correlated systemic microbial-associated inflammatory markers comparing first-time surgery and relapse clinical conditions.MethodsWe enrolled 28 CD patients at surgery; we collected inflamed and non-inflamed mucosa tissues and blood samples from each patient. Bacterial wall adherence was observed histologically, while its composition was assessed through amplicon sequencing of the 16S rRNA gene. In addition, we evaluated the systemic microRNA (miRNA) using quantitative real-time PCR amplification and free fatty acids (FFAs) using gas chromatography–mass spectroscopy.ResultsThe total number of mucosal adherent microbiota was enriched in healthy compared to inflamed mucosa. In contrast, the phylum Tenericutes, the family Ruminococcaceae, and the genera Mesoplasma and Mycoplasma were significantly enriched in the pathological setting. Significant microbiota differences were observed between the relapse and first surgery patients regarding the families Bacillaceae 2 and Brucellaceae and the genera Escherichia/Shigella, Finegoldia, Antrobacter, Gemmatimonas, Moraxella, Anoxibacillus, and Proteus. At the systemic level, we observed a significant downregulation of circulating miR-155 and miR-223, as well as 2-methyl butyric, isobutyric, and hexanoic (caproic) acids in recurrence compared to the first surgery patients. In addition, the level of hexanoic acid seems to act as a predictor of recurrence risk in CD patients (OR 18; 95% confidence interval 1.24–261.81; p = 0.006).ConclusionsWe describe a dissimilarity of ileal microbiota composition comparing CD and healthy settings, as well as systemic microbial-associated inflammatory factors between first surgery and surgical relapse. We suggest that patterns of microbiota, associated with healthy ileal tissue, could be involved in triggering CD recurrence. Our findings may provide insight into the dynamics of the gut microbiota–immunity axis in CD surgical recurrence, paving the way for new diagnostics and therapeutics aimed not only at reducing inflammation but also at maintaining a general state of eubiosis in healthy tissue.

In recent years, algorithmic-based market manipulation in stock and power markets has considerably increased, and it is difficult to identify all such manipulation cases. This causes serious challenges for market regulators. This work highlights and lists various aspects of the monitoring of stock and power markets, using as test cases the regulatory agencies and regulatory policies in diverse regions, including Hong Kong, the United Kingdom, the United States and the European Union. Reported cases of market manipulations in the regions are examined. In order to help establish a relevant digital regulatory system, this work reviews and categorizes the indicators used to monitor the stock and power markets, and provides an in-depth analysis of the relationship between the indicators and market manipulation. This study specifically compiles a set of 10 indicators for detecting manipulation in the stock market, utilizing the perspectives of return rate, liquidity, volatility, market sentiment, closing price and firm governance. Additionally, 15 indicators are identified for detecting manipulation in the power market, utilizing the perspectives of market power (also known as pricing power or market structure), market conduct and market performance. Finally, the study elaborates on the current challenges in the regulation of stock and power markets in terms of parameter performance, data availability and technical requirements.

A major depressive disorder is a serious mental illness characterized by a pervasive low mood that negatively concerns personal life, work life, or education, affecting millions of people worldwide. To date, due to the complexity of the disease, the most common and effective treatments consist of a multi-therapy approach, including psychological, social, and pharmacological support with antidepressant drugs. In general, antidepressants are effective in correcting chemical imbalances of neurotransmitters in the brain, but recent evidence has underlined the pivotal role of gut microbiota (GM) also in the regulation of their pharmacokinetics/pharmacodynamics, through indirect or direct mechanisms. The study of these complex interactions between GM and drugs is currently under the spotlight, and it has been recently named “pharmacomicrobiomics”. Hence, the purpose of this review is to summarize the contribution of GM and its metabolites in depression, as well as their role in the metabolism and activity of antidepressant drugs, in order to pave the way for the personalized administration of antidepressant therapies.

Lignans are non-flavonoid polyphenols present in a wide range of foods frequently consumed in the Western world, such as seeds, vegetables and fruits, and beverages such as coffee, tea and wine. In particular, the human gut microbiota (GM) can convert dietary lignans into biologically active compounds, especially enterolignans (i.e., enterolactone and enterodiol), which play anti-inflammatory and anti-oxidant roles, act as estrogen receptor activators and modulate gene expression and/or enzyme activity. Interestingly, recent evidence documenting those dietary interventions involving foods enriched in lignans have shown beneficial and protective effects on various human pathologies, including colorectal and breast cancer and cardiovascular diseases. However, considering that more factors (e.g., diet, food transit time and intestinal redox state) can modulate the lignans bioactivation by GM, there are usually remarkable inter-individual differences in urine, fecal and blood concentrations of enterolignans; hence, precise and validated analytical methods, especially gas/liquid chromatography coupled to mass spectrometry, are needed for their accurate quantification. Therefore, this review aims to summarize the beneficial roles of enterolignans, their interaction with GM and the new methodological approaches developed for their evaluation in different biological samples, since they could be considered future promising nutraceuticals for the prevention of human chronic disorders.

Background and aimGut microbiota (GM) can support colorectal cancer (CRC) progression by modulating immune responses through the production of both immunostimulatory and/or immunosuppressive cytokines. The role of IL-9 is paradigmatic because it can either promote tumor progression in hematological malignancies or inhibit tumorigenesis in solid cancers. Therefore, we investigate the microbiota–immunity axis in healthy and tumor mucosa, focusing on the correlation between cytokine profile and GM signature.MethodsIn this observational study, we collected tumor (CRC) and healthy (CRC-S) mucosa samples from 45 CRC patients, who were undergoing surgery in 2018 at the Careggi University Hospital (Florence, Italy). First, we characterized the tissue infiltrating lymphocyte subset profile and the GM composition. Subsequently, we evaluated the CRC and CRC-S molecular inflammatory response and correlated this profile with GM composition, using Dirichlet multinomial regression.ResultsCRC samples displayed higher percentages of Th17, Th2, and Tregs. Moreover, CRC tissues showed significantly higher levels of MIP-1α, IL-1α, IL-1β, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, P-selectin, and IL-9. Compared to CRC-S, CRC samples also showed significantly higher levels of the following genera: Fusobacteria, Proteobacteria, Fusobacterium, Ruminococcus2, and Ruminococcus. Finally, the abundance of Prevotella spp. in CRC samples negatively correlated with IL-17A and positively with IL-9. On the contrary, Bacteroides spp. presence negatively correlated with IL-9.ConclusionsOur data consolidate antitumor immunity impairment and the presence of a distinct microbiota profile in the tumor microenvironment compared with the healthy mucosa counterpart. Relating the CRC cytokine profile with GM composition, we confirm the presence of bidirectional crosstalk between the immune response and the host’s commensal microorganisms. Indeed, we document, for the first time, that Prevotella spp. and Bacteroides spp. are, respectively, positively and negatively correlated with IL-9, whose role in CRC development is still under debate.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A genome-wide association study showed a correlation between ANCA-negative EGPA and variants of genes encoding proteins with intestinal barrier functions, suggesting that modifications of the mucosal layer and consequent gut dysbiosis might be involved in EGPA pathogenesis. Here, we characterized the gut microbiota (GM) composition and the intestinal immune response in a cohort of EGPA patients. Faeces from 29 patients and 9 unrelated healthy cohabitants were collected, and GM and derived metabolites’ composition were compared. Seven intestinal biopsies from EGPA patients with gastrointestinal manifestations were analysed to assess the T-cell distribution and its correlation with GM and EGPA clinical and laboratory features. No significant differences in GM composition, nor in the total amount of faecal metabolites, emerged between patients and controls. Nevertheless, differences in bacterial taxa abundances and compositional GM-derived metabolites profile were observed. Notably, an enrichment of potential pathobionts (Enterobacteriacee and Streptococcaceae) was found in EGPA, particularly in patients with active disease, while lower levels were found in patients on immunosuppression, compared with non-immunosuppressed ones. Significantly lower amounts of hexanoic acid were found in patients, compared to controls. The analysis of the immune response in the gut mucosa revealed a high frequency of IFN-γ/IL-17-producing T lymphocytes, and a positive correlation between EGPA disease activity and intestinal T-cell levels. Our data suggest that an enrichment in potential intestinal pathobionts might drive an imbalanced inflammatory response in EGPA.

The Energy Management System (EMS) is an efficient technique to monitor, control and enhance the building performance. In the state-of-the-art, building performance analysis is separated into building simulation and control management: this may cause inaccuracies and extra operating time. Thus, a coherent framework to integrate building physics with various energy technologies and energy control management methods is highly required. This framework should be formed by simplified but accurate models of building physics and building energy technologies, and should allow for the selection of proper control strategies according to the control objectives and scenarios. Therefore, this paper reviews the fundamental mathematical modeling and control strategies to create such a framework. The mathematical models of (i) building physics and (ii) popular building energy technologies (renewable energy systems, common heating and cooling energy systems and energy distribution systems) are first presented. Then, it is shown how the collected mathematical models can be linked. Merging with two frequently used EMS strategies, namely rule-based and model predictive controls, is discussed. This work provides an extendable map to model and control buildings and intends to be a foundation for building researchers, designers and engineers.

The existing literature on energy saving focuses on large-scale buildings, wherein the energy-saving potential is substantially larger than smaller-scale buildings. However, the research intensity is significantly less for small-scale deployments and their capacities to regulate energy use individually, directly and without depreciating users’ comfort and needs. The current research effort focused on energy saving and user satisfaction, concerning a low-cost—yet technically sophisticated—methodology for controlling conventional residential HVAC units through cheap yet reliable actuation and sensing and auxiliary IoT equipment. The basic ingredients of the proposed experimental methodology involve a conventional A/C unit, an Arduino microcontroller, typical wireless IoT sensors and actuators, a configured graphical environment and a sophisticated, model-free, optimization-and-control algorithm (PCAO) that portrays the ground basis for achieving improved performance results in comparison with conventional methods. The main goal of this study was to produce a system that would adequately and expeditiously achieve energy savings by utilizing minimal hardware/equipment (affordability). The system was designed to be easily expandable in terms of new units or thermal equipment (expandability) and also to be autonomous, requiring zero user interventions at the experimental site (automation). The real-life measurements were collected over two different seasonal periods of the year (winter, summer) and concerned a conventional apartment in the city of Xanthi, Northern Greece, where summers and winters exhibit quite diverse climate characteristics. The final results revealed the increased efficiency of PCAO’s optimization in comparison with a conventional rule-based control strategy (RBC), as concerns energy savings and user satisfaction.

Persistent infection with High Risk-Human Papilloma Viruses (HR-HPVs) is a primary cause of cervical cancer worldwide. Vaginal-dysbiosis-associated bacteria were correlated with the persistence of HR-HPVs infection and with increased cancer risk. We obtained strains of the most represented bacterial species in vaginal microbiota and evaluated their effects on the survival of cervical epithelial cells and immune homeostasis. The contribution of each species to supporting the antiviral response was also studied. Epithelial cell viability was affected by culture supernatants of most vaginal-dysbiosis bacteria, whereas Lactobacillus gasseri or Lactobacillus jensenii resulted in the best stimulus to induce interferon-γ (IFN-γ) production by human mononuclear cells from peripheral blood (PBMCs). Although vaginal-dysbiosis-associated bacteria induced the IFN-γ production, they were also optimal stimuli to interleukin-17 (IL-17) production. A positive correlation between IL-17 and IFN-γ secretion was observed in cultures of PBMCs with all vaginal-dysbiosis-associated bacteria suggesting that the adaptive immune response induced by these strains is not dominated by TH1 differentiation with reduced availability of IFN-γ, cytokine most effective in supporting virus clearance. Based on these results, we suggest that a vaginal microbiota dominated by lactobacilli, especially by L. gasseri or L. jensenii, may be able to assist immune cells with clearing HPV infection, bypasses the viral escape and restores immune homeostasis.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity axis in the pathogenesis of neurodegenerative diseases. In the present study, we compared the inflammatory and microbiota profile of ALS patients with different clinical characteristics, with healthy family caregivers. Measuring a panel of 30 inflammatory cytokines in serum and fecal samples, we observed a distinct cytokine profile both at the systemic and intestinal level in patients compared to controls and even in patients with different clinical phenotypes and progression rates. The 16S targeted metagenome analysis revealed slight differences in patients compared to controls as well as in patients with slow progression, marked by the reduction of butyrate-producing bacteria and a decrease of the Firmicutes/Bacteroidetes ratio in ALS. Finally, the short chain fatty acid analysis did not show a different distribution among the groups. If confirmed in a larger number of patients, the inflammatory cytokine profile and the microbial composition could be appropriate biomarker candidates for deciphering ALS heterogeneity.

Altered circulating levels of free fatty acids (FFAs), namely short chain fatty acids (SCFAs), medium chain fatty acids (MCFAs), and long chain fatty acids (LCFAs), are associated with metabolic, gastrointestinal, and malignant diseases. Hence, we compared the serum FFA profile of patients with celiac disease (CD), adenomatous polyposis (AP), and colorectal cancer (CRC) to healthy controls (HC). We enrolled 44 patients (19 CRC, 9 AP, 16 CD) and 16 HC. We performed a quantitative FFA evaluation with the gas chromatography–mass spectrometry method (GC–MS), and we performed Dirichlet-multinomial regression in order to highlight disease-specific FFA signature. HC showed a different composition of FFAs than CRC, AP, and CD patients. Furthermore, the partial least squares discriminant analysis (PLS-DA) confirmed perfect overlap between the CRC and AP patients and separation of HC from the diseased groups. The Dirichlet-multinomial regression identified only strong positive association between CD and butyric acid. Moreover, CD patients showed significant interactions with age, BMI, and gender. In addition, among patients with the same age and BMI, being male compared to being female implies a decrease of the CD effect on the (log) prevalence of butyric acid in FFA composition. Our data support GC–MS as a suitable method for the concurrent analysis of circulating SCFAs, MCFAs, and LCFAs in different gastrointestinal diseases. Furthermore, and notably, we suggest for the first time that butyric acid could represent a potential biomarker for CD screening.

Unmanned Aerial Vehicles (UAVs) have multi-domain applications, fixed-wing UAVs being a widely used class. Despite the ongoing research on the topics of guidance and formation control of fixed-wing UAVs, little progress is known on implementation of semi-physical validation platforms (software-in-the-loop or hardware-in-the-loop) for such complex autonomous systems. A semi-physical simulation platform should capture not only the physical aspects of UAV dynamics, but also the cybernetics aspects such as the autopilot and the communication layers connecting the different components. Such a cyber-physical integration would allow validation of guidance and formation control algorithms in the presence of uncertainties, unmodelled dynamics, low-level control loops, communication protocols and unreliable communication: These aspects are often neglected in the design of guidance and formation control laws for fixed-wing UAVs. This paper describes the development of a semi-physical platform for multi-fixed wing UAVs where all the aforementioned points are carefully integrated. The environment adopts Raspberry Pi’s programmed in C++, which can be interfaced to standard autopilots (PX4) as a companion computer. Simulations are done in a distributed setting with a server program designed for the purpose of routing data between nodes, handling the user inputs and configurations of the UAVs. Gazebo-ROS is used as a 3D visualization tool.

Adaptive mixing control (AMC) is a recently developed control scheme for uncertain plants, where the control action coming from a bank of precomputed controller is mixed based on the parameter estimates generated by an on-line parameter estimator. Even if the stability of the control scheme, also in the presence of modeling errors and disturbances, has been shown analytically, its transient performance might be sensitive to the initial conditions of the parameter estimator. In particular, for some initial conditions, transient oscillations may not be acceptable in practical applications. In order to account for such a possible phenomenon and to improve the learning capability of the adaptive scheme, in this paper a new mixing architecture is developed, involving the use of parallel parameter estimators, or multi-estimators, each one working on a small subset of the uncertainty set. A supervisory logic, using performance signals based on the past and present estimation error, selects the parameter estimate to determine the mixing of the controllers. The stability and robustness properties of the resulting approach, referred to as multi-estimator adaptive mixing control (Multi-AMC), are analytically established. Besides, extensive simulations demonstrate that the scheme improves the transient performance of the original AMC with a single estimator. The control scheme and the analysis are carried out in a discrete-time framework, for easier implementation of the method in digital control.

Heating, ventilation and air-conditioning (HVAC) units in buildings form a system-of-subsystems entity that must be accurately integrated and controlled by the building automation system to ensure the occupants’ comfort with reduced energy consumption. As control of HVACs involves a standardized hierarchy of high-level set-point control and low-level Proportional-Integral-Derivative (PID) controls, there is a need for overcoming current control fragmentation without disrupting the standard hierarchy. In this work, we propose a model-based approach to achieve these goals. In particular: the set-point control is based on a predictive HVAC thermal model, and aims at optimizing thermal comfort with reduced energy consumption; the standard low-level PID controllers are auto-tuned based on simulations of the HVAC thermal model, and aims at good tracking of the set points. One benefit of such control structure is that the PID dynamics are included in the predictive optimization: in this way, we are able to account for tracking transients, which are particularly useful if the HVAC is switched on and off depending on occupancy patterns. Experimental and simulation validation via a three-room test case at the Delft University of Technology shows the potential for a high degree of comfort while also reducing energy consumption.

This work is meant to report on activities at TU Delft on the design and implementation of a path-following system for an autonomous Toyota Prius. The design encompasses: finding the vehicle parameters for the actual vehicle to be used for control design; lateral and longitudinal controllers for steering and acceleration, respectively. The implementation covers the real-time aspects via LabVIEW from National Instruments and the real-life tests. The deployment of the system was enabled by a Spatial Dual Global Positioning System (GPS) system providing more accuracy than the regular GPS. The results discussed in this work represent the first autonomous tests on the Toyota Prius at TU Delft, and we expect the proposed system to be a benchmark against which to test more advanced solutions. The tests show that the system is able to perform in real-time while satisfying comfort and trajectory tracking requirements: in particular, the tracking error was within 16 cm, which is compatible with the 13 cm precision of the Spatial Dual GPS, whereas the longitudinal and lateral acceleration are within comfort levels as defined by available experimental studies.

Condensing boilers use waste heat from flue gases to pre-heat cold water entering the boiler. Flue gases are condensed into liquid form, thus recovering their latent heat of vaporization, which results in as much as 10%–12% increase in efficiency. Modeling these heat transfer phenomena is crucial to control this equipment. Despite the many approaches to the condensing boiler modeling, the following shortcomings are still not addressed: thermal dynamics are oversimplified with a nonlinear efficiency curve (which is calculated at steady-state); the dry/wet heat exchange is modeled in a fixed proportion. In this work we cover these shortcomings by developing a novel hybrid dynamic model which avoids the static nonlinear efficiency curve and accounts for a time-varying proportion of dry/wet heat exchange. The procedure for deriving the model is described and the efficiency of the resulting condensing boiler is shown.

Several multiple model adaptive control architectures have been proposed in the literature. Despite many advances in theory, the crucial question of how to synthesize the pairs model/controller in a structurally optimal way is to a large extent not addressed. In particular, it is not clear how to place the pairs model/controller is such a way that the properties of the switching algorithm (e.g., number of switches, learning transient, final performance) are optimal with respect to some criteria. In this work, we focus on the so-called multi-model unfalsified adaptive supervisory switching control (MUASSC) scheme; we define a suitable structural optimality criterion and develop algorithms for synthesizing the pairs model/controller in such a way that they are optimal with respect to the structural optimality criterion we defined. The peculiarity of the proposed optimality criterion and algorithms is that the optimization is carried out so as to optimize the entire behavior of the adaptive algorithm, i.e., both the learning transient and the steady-state response. A comparison is made with respect to the model distribution of the robust multiple model adaptive control (RMMAC), where the optimization considers only the steady-state ideal response and neglects any learning transient.