Disease Tolerance as an Inherent Component of Immunity.

Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.

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.

Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions.

Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.

Inner ear biomechanics reveals a Late Triassic origin for mammalian endothermy.

Endothermy underpins the ecological dominance of mammals and birds in diverse environmental settings1,2. However, it is unclear when this crucial feature emerged during mammalian evolutionary history, as most of the fossil evidence is ambiguous3-17. Here we show that this key evolutionary transition can be investigated using the morphology of the endolymph-filled semicircular ducts of the inner ear, which monitor head rotations and are essential for motor coordination, navigation and spatial awareness18-22. Increased body temperatures during the ectotherm-endotherm transition of mammal ancestors would decrease endolymph viscosity, negatively affecting semicircular duct biomechanics23,24, while simultaneously increasing behavioural activity25,26 probably required improved performance27. Morphological changes to the membranous ducts and enclosing bony canals would have been necessary to maintain optimal functionality during this transition. To track these morphofunctional changes in 56 extinct synapsid species, we developed the thermo-motility index, a proxy based on bony canal morphology. The results suggest that endothermy evolved abruptly during the Late Triassic period in Mammaliamorpha, correlated with a sharp increase in body temperature (5-9 °C) and an expansion of aerobic and anaerobic capacities. Contrary to previous suggestions3-14, all stem mammaliamorphs were most probably ectotherms. Endothermy, as a crucial physiological characteristic, joins other distinctive mammalian features that arose during this period of climatic instability28.

Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme.

Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., Nat. Immunol. 22, 2-6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular "labile" heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M. T. Bozza, Curr. Opin. Immunol. 38, 94-100 (2016)]. Here, we report that labile heme is a previously unrecognized inducer of trained immunity that confers long-term regulation of lineage specification of hematopoietic stem cells and progenitor cells. In contrast to previous reports on trained immunity, essentially mediated by pathogen-associated molecular patterns, heme training depends on spleen tyrosine kinase signal transduction pathway acting upstream of c-Jun N-terminal kinases. Heme training promotes resistance to sepsis, is associated with the expansion of self-renewing hematopoetic stem cells primed toward myelopoiesis and to the occurrence of a specific myeloid cell population. This is potentially evoked by sustained activity of Nfix, Runx1, and Nfe2l2 and dissociation of the transcriptional repressor Bach2. Previously reported trained immunity inducers are, however, infrequently present in the host, whereas heme abundantly occurs during noninfectious and infectious disease. This difference might explain the vanishing protection exerted by heme training in sepsis over time with sustained long-term myeloid adaptations. Hence, we propose that trained immunity is an integral component of innate immunity with distinct functional differences on infectious disease outcome depending on its induction by pathogenic or endogenous molecules.

Spatio-temporal trends of the age-at-menarche percentiles among Portuguese women since 1920.

BACKGROUND: This work aims to study the spatio-temporal evolution of a woman's age at menarche in the central region of Portugal. One of the concerns of the study is early or late menarches; thus, we consider percentile regression to build the respective curves as opposed to the more traditional mean regression approach. METHODS: We analysed the data from [Formula: see text] women born in the period 1920-1973 who attended a free breast cancer screening program between 1990 and 2019. Distributional regression models inside the package GAMLSS in R were considered. These methods allowed us not only to model the location (mean) of the specific probability distribution of the age at menarche, but also allowed for the scale (variance) parameter of this distribution to depend on covariates. Additionally, a spatial random-effect was considered in order to capture the correlation at the regional level. The obtained clustered spatial effects were analysed to assess geographical differences among the percentiles of the age at menarche by year of birth. RESULTS: A decreasing trend in the age at menarche (about 1.5 years in 5 decades) and regional differences for all the considered percentiles were found. Women living in the north-central areas of the central region of Portugal tend to have menarche at older ages. CONCLUSION: We obtained percentile estimates for the age at menarche by year of birth and region of residence and demonstrated that these two explanatory variables have an impact on the explanation about the decreasing trend in age at a woman's first menstruation.

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis.

Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15, and that Gdf15-deficient mice are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum, leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.

Fish By-Products: A Source of Enzymes to Generate Circular Bioactive Hydrolysates.

Fish viscera are usually discarded as waste, causing environmental problems, or as low-value by-products. This study describes a self-sufficient and zero waste approach to obtain enzymes and protein hydrolysates from fish by-products. Firstly, recovery steps of viscera enzymatic extract were applied, and the resulting raw extract was stable at a pH range of 8-9 and at temperatures between 40 and 50 °C. The application of the extracted enzymes and alcalase on fish by-products hydrolysis was also determined. The selected conditions for the enzymatic hydrolysis were 10% (E/S) for 6 h using viscera enzymatic extract and 3% (E/S) for 2 h using alcalase. Fish protein hydrolysates (FPH) proved to have a notable antioxidant capacity with similar activity, ~11 mg ascorbic acid/g dry extract (ABTS assay) and ~150 mg Trolox/g dry extract (ORAC assay). FPH were also able to inhibit the angiotensin-converting enzyme, however, alcalase hydrolysates revealed a higher antihypertensive potential, IC50 of 101 µg of protein/mL. In general, FPH obtained by both enzymes systems maintained these bioactivities after the passage throughout a simulated gastrointestinal tract. The hydrolysates also displayed important technological properties, namely oil absorption capacity (~1 g oil/g sample) and emulsifying property (~40%). Therefore, it will be conceivable to use fish by-products based on a circular economy approach to generate added value compounds for animal and human nutrition.

Is age at menopause decreasing? - The consequences of not completing the generational cohort.

BACKGROUND: Due to contradictory results in current research, whether age at menopause is increasing or decreasing in Western countries remains an open question, yet worth studying as later ages at menopause are likely to be related to an increased risk of breast cancer. Using data from breast cancer screening programs to study the temporal trend of age at menopause is difficult since especially younger women in the same generational cohort have often not yet reached menopause. Deleting these younger women in a breast cancer risk analyses may bias the results. The aim of this study is therefore to recover missing menopause ages as a covariate by comparing methods for handling missing data. Additionally, the study makes a contribution to understanding the evolution of age at menopause for several generations born in Portugal between 1920 and 1970. METHODS: Data from a breast cancer screening program in Portugal including 278,282 women aged 45-69 and collected between 1990 and 2010 are used to compare two approaches of imputing age at menopause: (i) a multiple imputation methodology based on a truncated distribution but ignoring the mechanism of missingness; (ii) a copula-based multiple imputation method that simultaneously handles the age at menopause and the missing mechanism. The linear predictors considered in both cases have a semiparametric additive structure accommodating linear and non-linear effects defined via splines or Markov random fields smoothers in the case of spatial variables. RESULTS: Both imputation methods unveiled an increasing trend of age at menopause when viewed as a function of the birth year for the youngest generation. This trend is hidden if we model only women with an observed age at menopause. CONCLUSION: When studying age at menopause, missing ages must be recovered with an adequate procedure for incomplete data. Imputing these missing ages avoids excluding the younger generation cohort of the screening program in breast cancer risk analyses and hence reduces the bias stemming from this exclusion. In addition, imputing the not yet observed ages of menopause for mostly younger women is also crucial when studying the time trend of age at menopause otherwise the analysis will be biased.

Renal control of disease tolerance to malaria.

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.

A Fully-Integrated Ambient RF Energy Harvesting System with 423-µW Output Power.

This paper proposes a 2.4-GHz fully-integrated single-frequency multi-channel RF energy harvesting (RFEH) system with increased harvested power density. The RFEH can produce an output power of ~423-µW in harvesting ambient RF energy. The front-end consists of an on-chip impedance matching network with a stacked rectifier concurrently matched to a 50 Ω input source. The circuit mitigates the "dead-zone" by enhancing the pumping efficiency, achieved through the increase of Vgs drivability of the proposed internal gate boosting 6-stage low-input voltage charge pump and the 5-stage shared-auxiliary-biasing ring-voltage-controlled-oscillator (VCO) integrated to improve the start-up. The RFEH system, simulated in 180-nm complementary metal-oxide-semiconductor (CMOS), occupies an active area of 1.02 mm2. Post-layout simulations show a peak power conversion efficiency(PCE) of 21.15%, driving a 3.3-kΩ load at an input power of 0 dBm and sensitivity of -14.1 dBm corresponding to an output voltage, Vout,RFEH of 1.25 V.

A Reference Architecture for Cloud-Edge Meta-Operating Systems Enabling Cross-Domain, Data-Intensive, ML-Assisted Applications: Architectural Overview and Key Concepts.

Future data-intensive intelligent applications are required to traverse across the cloud-to-edge-to-IoT continuum, where cloud and edge resources elegantly coordinate, alongside sensor networks and data. However, current technical solutions can only partially handle the data outburst associated with the IoT proliferation experienced in recent years, mainly due to their hierarchical architectures. In this context, this paper presents a reference architecture of a meta-operating system (RAMOS), targeted to enable a dynamic, distributed and trusted continuum which will be capable of facilitating the next-generation smart applications at the edge. RAMOS is domain-agnostic, capable of supporting heterogeneous devices in various network environments. Furthermore, the proposed architecture possesses the ability to place the data at the origin in a secure and trusted manner. Based on a layered structure, the building blocks of RAMOS are thoroughly described, and the interconnection and coordination between them is fully presented. Furthermore, illustration of how the proposed reference architecture and its characteristics could fit in potential key industrial and societal applications, which in the future will require more power at the edge, is provided in five practical scenarios, focusing on the distributed intelligence and privacy preservation principles promoted by RAMOS, as well as the concept of environmental footprint minimization. Finally, the business potential of an open edge ecosystem and the societal impacts of climate net neutrality are also illustrated.

Dynamic prediction based on variability of a longitudinal biomarker.

BACKGROUND: Tacrolimus is given post-kidney transplant to suppress the immune system, and the amount of drug in the body is measured frequently. Higher variability over time may be indicative of poor drug adherence, leading to more adverse events. It is important to account for the variation in Tacrolimus, not just the average change over time. METHODS: Using data from the University of Colorado, we compare methods of assessing how the variability in Tacrolimus influences the hazard of de novo Donor Specific Antibodies (dnDSA), an early warning sign of graft failure. We compare multiple joint models in terms of fit and predictive ability. We explain that the models that account for the individual-specific variability over time have the best predictive performance. These models allowed each patient to have an individual-specific random error term in the longitudinal Tacrolimus model, and linked this to the hazard of dnDSA model. RESULTS: The hazard for the variance and coefficient of variation (CV) loading parameter were greater than 1, indicating that higher variability of Tacrolimus had a higher hazard of dnDSA. Introducing the individual-specific variability improved the fit, leading to more accurate predictions about the individual-specific time-to-dnDSA. CONCLUSIONS: We showed that the individual's variability in Tacrolimus is an important metric in predicting long-term adverse events in kidney transplantation. This is an important step in personalizing the dosage of TAC post-transplant to improve outcomes post-transplant.

Left atrial functional assessment and mortality in patients with severe aortic stenosis with sinus rhythm.

BACKGROUND: Aortic valve stenosis (AS) is the most common primary valvular heart disease leading to surgical or percutaneous aortic valve replacement (AVR) in Europe and its prevalence keeps growing. While other risk factors in severe AS are well documented, little is known about the prognostic value of left atrial (LA) function in AS. Our aim is to clarify the relationship between LA function measured at severe AS diagnosis (evaluated by means of volumetric assessment) and all-cause mortality during follow-up. METHODS: We retrospectively evaluated patients diagnosed with severe AS for the first time at our echocardiography laboratory. We evaluated LA reservoir, conduit and pump function by measuring LA volumes at different timings of cardiac cycle. Treatment strategy was decided according to heart team consensus and patient decision. We divided patients into groups according to terciles of LA reservoir, conduit and pump function. Primary outcome was defined by the occurrence of all-cause mortality during follow-up. RESULTS: A total of 408 patients were included in the analysis, with a median follow-up time of 45 months (interquartile range 54 months). 57.9% of patients underwent AVR and 44.9% of patients registered the primary outcome during follow-up. Left atrial emptying fraction (LAEF) was the best LA functional parameter and the best overall parameter in discriminating primary outcome (AUC 0.845, 95%CI 0.81-0.88, P < 0.001). After adjustment for clinical, demographic and echocardiographic variables, cumulative survival of patients with LAEF < 37% and LAEF 37 to 53% relative to patients with LAEF ≥54% remained significantly lower (HR 13.91, 95%CI 6.20-31.19, P < 0.001 and HR 3.40, 95%CI 1.57-7.37, P = 0.002, respectively). After adjustment for AVR, excess risk of LAEF < 37% and LAEF 37 to 53% relative to LAEF ≥54% remained significant (HR 11.71, 95%CI 5.20-26.40, P < 0.001 and HR 3.59, 95%CI 1.65-7.78, P = 0.001, respectively). CONCLUSIONS: In patients with a first diagnosis of severe AS, LA function, evaluated by means of volumetric assessment, is an independent predictor of all-cause mortality and a more potent predictor of death compared to classical severity parameters. These data can be useful to identify high-risk patients who might benefit of AVR.

Supported TiO2 in Ceramic Materials for the Photocatalytic Degradation of Contaminants of Emerging Concern in Liquid Effluents: A Review.

The application of TiO2 as a slurry catalyst for the degradation of contaminants of emerging concern (CEC) in liquid effluents has some drawbacks due to the difficulties in the catalyst reutilization. Thus, sophisticated and expensive separation methods are required after the reaction step. Alternatively, several types of materials have been used to support powder catalysts, so that fixed or fluidized bed reactors may be used. In this context, the objective of this work is to systematize and analyze the results of research inherent to the application of ceramic materials as support of TiO2 in the photocatalytic CEC removal from liquid effluents. Firstly, an overview is given about the treatment processes able to degrade CEC. In particular, the photocatalysts supported in ceramic materials are analyzed, namely the immobilization techniques applied to support TiO2 in these materials. Finally, a critical review of the literature dedicated to photocatalysis with supported TiO2 is presented, where the performance of the catalyst is considered as well as the main drivers and barriers for implementing this process. A focal point in the future is to investigate the possibility of depurating effluents and promote water reuse in safe conditions, and the supported TiO2 in ceramic materials may play a role in this scope.

Synthesis of Catechol Derived Rosamine Dyes and Their Reactivity toward Biogenic Amines.

Functional organic dyes play a key role in many fields, namely in biotechnology and medical diagnosis. Herein, we report two novel 2,3- and 3,4-dihydroxyphenyl substituted rosamines (3 and 4, respectively) that were successfully synthesized through a microwave-assisted protocol. The best reaction yields were obtained for rosamine 4, which also showed the most interesting photophysical properties, specially toward biogenic amines (BAs). Several amines including n- and t-butylamine, cadaverine, and putrescine cause spectral changes of 4, in UV-Vis and fluorescence spectra, which are indicative of their potential application as an effective tool to detect amines in acetonitrile solutions. In the gas phase, the probe response is more expressive for spermine and putrescine. Additionally, we found that methanolic solutions of rosamine 4 and n-butylamine undergo a pink to yellow color change over time, which has been attributed to the formation of a new compound. The latter was isolated and identified as 5 (9-aminopyronin), whose solutions exhibit a remarkable increase in fluorescence intensity together with a shift toward more energetic wavelengths. Other 9-aminopyronins 6a, 6b, 7a, and 7b were obtained from methanolic solutions of 4 with putrescine and cadaverine, demonstrating the potential of this new xanthene entity to react with primary amines.

Portable NMR with Parallelism.

Portable NMR combining a permanent magnet and a complementary metal-oxide-semiconductor (CMOS) integrated circuit has recently emerged to offer the long desired online, on-demand, or in situ NMR analysis of small molecules for chemistry and biology. Here we take this cutting-edge technology to the next level by introducing parallelism to a state-of-the-art portable NMR platform to accelerate its experimental throughput, where NMR is notorious for inherently low throughput. With multiple (N) samples inside a single magnet, we perform simultaneous NMR analyses using a single silicon electronic chip, going beyond the traditional single-sample-per-magnet paradigm. We execute the parallel analyses via either time-interleaving or magnetic resonance imaging (MRI). In the time-interleaving method, the N samples occupy N separate NMR coils: we connect these N NMR coils to the single silicon chip one after another and repeat these sequential NMR scans. This time-interleaving is an effective parallelization, given a long recovery time of a single NMR scan. To demonstrate this time-interleaved parallelism, we use N = 2 for high-resolution multidimensional spectroscopy such as J-coupling resolved free induction decay spectroscopy and correlation spectroscopy (COSY) with the field homogeneity carefully optimized (<0.16 ppm) and N = 4 for multidimensional relaxometry such as diffusion-edited T2 mapping and T1-T2 correlation mapping, expediting the throughput by 2-4 times. In the MRI technique, the N samples (N = 18 in our demonstration) share 1 NMR coil connected to the single silicon chip and are imaged all at once multiple times, which reveals the relaxation time of all N samples simultaneously. This imaging-based approach accelerates the relaxation time measurement by 4.5 times, and it could be by 18 times if the signal-to-noise were not limited. Overall, this work demonstrates the first portable high-resolution multidimensional NMR with throughput-accelerating parallelism.

Removal of a mixture of pharmaceuticals sulfamethoxazole and diclofenac from water streams by a polyamide nanofiltration membrane.

Wastewater treatment plants are not specially designed to remove pharmaceutically active compounds (PhACs), since these substances are toxic and bio-refractory. This paper aims to investigate and optimize the performance of the Trisep TS80 nanofiltration (NF) membrane for the removal of a mixture of two of the most detected PhACs in municipal wastewaters worldwide, sulfamethoxazole and diclofenac. Several NF tests were carried out to study the rejections of these contaminants both spiked in demineralized water, filtrated water taken from Mondego River and secondary effluent coming from a municipal wastewater treatment plant. Among the several studied operating variables, pH was the one that most affected the contaminant rejection and membrane permeability. In the case of synthetic effluent, an applied pressure of 10 bar and pH 7 were determined as the best operating conditions, which allowed almost total chemical oxygen demand retention and a global contaminant rejection of 96.3% to be achieved. The application of different water matrices (river water and secondary municipal effluent) had no relevant impact on process efficiency. Vibrio fischeri luminescence inhibition tests revealed that treatment by nanofiltration reduced acute toxicity of all studied effluents.