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Topology optimization problem formulations have lately included stresses, besides compliance, to ensure mechanical strength feasibility, which is of utmost importance in structural engineering practice. A mechanically induced stress field has often been considered in optimal structural design. However, one realizes that thermal stresses can also greatly influence efficient designs, especially when addressing highly constrained structures. Moreover, stress mitigation has been achieved by enlarging the design domain to multi-material solutions. This motivates to pursue stress-based topology optimization of thermoelastic structures and the extension of the multi-material setting to Functionally Graded Materials (FGMs), with greater potential in stress mitigation. Two optimization problems are investigated: (1) elastic strain energy minimization and (2) maximum von Mises stress minimization. In the former, the single-material problem is revisited, but in the frame of a multi-objective formulation, weighting mechanical and thermal strain energy terms, as they can be decoupled. Insights into thermal stresses allow to propose a well-posed stress-based formulation for the topology optimization thermoelastic problem. In the latter, stress mitigation is sought on account of optimizing the spatial mixture (composition) of two solids amidst prescribed or predicted voids. It is assumed that the RAMP interpolation scheme has the physical meaning of rendering the thermoelastic properties for the continuous variation of composition. Linear thermoelasticity and plane stress benchmarks are used. In the multi-objective energy-based problem, the trade-offs between the conflicting design objectives, in the Pareto sense, are highlighted. Regarding the stress-based problem, lower stress peaks are obtained in FGM solutions, as stresses are more evenly distributed.

Functionally Graded Materials (FGMs) can outperform their homogeneous counterparts. Advances in digitalization technologies, mainly additive manufacturing, have enabled the synthesis of materials with tailored properties and functionalities. Joining dissimilar metals to attain compositional grading is a relatively unexplored research area and holds great promise for engineering applications. Metallurgical challenges may arise; thus, a theoretical critical analysis is presented in this paper. A multidisciplinary methodology is proposed here to unify optimal design, multi-feed Wire-Arc Additive Manufacturing (WAAM), and image-based characterization methods to create structure-specific oriented FGM parts. Topology optimization is used to design FGMs. A beam under pure bending is used to explore the layer-wise FGM concept, which is also analytically validated. The challenges, limitations, and role of WAAM in creating FGM parts are discussed, along with the importance of numerical validation using full-field deformation data. As a result, a conceptual FGM engineering workflow is proposed at this stage, enabling digital data conversion regarding geometry and compositional grading. This is a step forward in processing in silico data, with a view to experimentally producing parts in future. An optimized FGM beam, revealing an optimal layout and a property gradient from iron to copper along the build direction (bottom–up) that significantly reduces the normal pure bending stresses (by 26%), is used as a case study to validate the proposed digital workflow.

Macrophages play an important role in immunity and homeostasis. Upon pathogen recognition via specific receptors, they rapidly induce inflammatory responses. This process is tightly controlled at the transcriptional level. The DNA binding zinc-finger protein CCCTC-binding factor （Ctcf） is a crucial regulator of long-range chromatin interactions and coordinates specific communication between transcription factors and gene expression processes. In this study, the Ctcf gene was specifically deleted in myeloid cells by making use of the transgenic Cre-LoxP system. Conditional deletion of the Ctcfgene in myeloid cells induced a mild phenotype in vivo. Ctcf-deficient mice exhibited significantly reduced expression of major histocompatibility complex （MHC） class II in the liver. Ctcf-deficient macrophages demonstrated a normal surface phenotype and phagocytosis capacity. Upon Toll-like receptor （TLR） stimulation, they produced normal levels of the pro-inflammatory cytokines IL-12 and IL-6, but manifested a strongly impaired capacity to produce tumor-necrosis factor （TNF） and IL-IO, as well as to express the IL-IO family members IL-19, IL-20 and IL-24. Taken together, our data demonstrate a role of Ctcf that involves fine-tuning of macrophage function.

Parkinson’s disease (PD) is an age-related neurodegenerative disease associated with the misfolding and aggregation of alpha-synuclein (aSyn). The molecular underpinnings of PD are still obscure, but nutrition may play an important role in the prevention, onset, and disease progression. Dietary (poly)phenols revert and prevent age-related cognitive decline and neurodegeneration in model systems. However, only limited attempts were made to evaluate the impact of digestion on the bioactivities of (poly)phenols and determine their mechanisms of action. This constitutes a challenge for the development of (poly)phenol-based nutritional therapies. Here, we subjected (poly)phenols from Arbutus unedo to in vitro digestion and tested the products in cell models of PD based on the cytotoxicity of aSyn. The (poly)phenol-digested metabolites from A. unedo leaves (LPDMs) effectively counteracted aSyn and H 2 O 2 toxicity in yeast and human cells, improving viability by reducing aSyn aggregation and inducing its clearance. In addition, LPDMs modulated pathways associated with aSyn toxicity, such as oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial impairment, and SIR2 expression. Overall, LPDMs reduced aSyn toxicity, enhanced the efficiency of ER-associated protein degradation by the proteasome and autophagy, and reduced oxidative stress. In total, our study opens novel avenues for the exploitation of (poly)phenols in nutrition and health.

Mitochondria are descendants of endosymbiotic bacteria and retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, mitochondrial DNA is subjected to bidirectional transcription that generates overlapping transcripts, which are capable of forming long double-stranded RNA structures 1 , 2 . However, to our knowledge, mitochondrial double-stranded RNA has not been previously characterized in vivo. Here we describe the presence of a highly unstable native mitochondrial double-stranded RNA species at single-cell level and identify key roles for the degradosome components mitochondrial RNA helicase SUV3 and polynucleotide phosphorylase PNPase in restricting the levels of mitochondrial double-stranded RNA. Loss of either enzyme results in massive accumulation of mitochondrial double-stranded RNA that escapes into the cytoplasm in a PNPase-dependent manner. This process engages an MDA5-driven antiviral signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in the gene PNPT1 , which encodes PNPase, display mitochondrial double-stranded RNA accumulation coupled with upregulation of interferon-stimulated genes and other markers of immune activation. The localization of PNPase to the mitochondrial inter-membrane space and matrix suggests that it has a dual role in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms that have evolved to protect vertebrates against microbial and viral attack. Mitochondrial double-stranded RNA can induce an interferon response if released into the cytoplasm, but self-recognition is prevented by SUV3 helicase and PNPase exoribonuclease.

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

Background Patients undergoing abdominal surgery for solid tumours frequently develop major postoperative complications, which negatively affect quality of life, costs of care and survival. Few studies have identified the determinants of perioperative complications in this group. Methods We performed a prospective observational study including all patients (age > 18) undergoing abdominal surgery for cancer at a single institution between June 2011 and August 2013. Patients undergoing emergency surgery, palliative procedures, or participating in other studies were excluded. Primary outcome was a composite of 30-day all-cause mortality and infectious, cardiovascular, respiratory, neurologic, renal and surgical complications. Univariate and multiple logistic regression analyses were performed to identify predictive factors for major perioperative adverse events. Results Of a total 308 included patients, 106 (34.4%) developed a major complication during the 30-day follow-up period. Independent predictors of postoperative major complications were: age (odds ratio [OR] 1.03 [95% CI 1.01–1.06], p  = 0.012 per year), ASA (American Society of Anesthesiologists) physical status greater than or equal to 3 (OR 2.61 [95% CI 1.33–5.17], p  = 0.003), a preoperative haemoglobin level lower than 12 g/dL (OR 2.13 [95% CI 1.21–4.07], p  = 0.014), intraoperative use of colloids (OR 1.89, [95% CI 1.03–4.07], p  = 0.047), total amount of intravenous fluids (OR 1.22 [95% CI 0.98–1.59], p  = 0.106 per litre), intraoperative blood losses greater than 500 mL (2.07 [95% CI 1.00–4.31], p  = 0.043), and hypotension needing vasopressor support (OR 4.68 [95% CI 1.55–27.72], p  = 0.004). The model had good discrimination with the area under the ROC curve being 0.80 (95% CI 0.75–0.84, p  < 0.001). Conclusions Our findings suggest that a perioperative strategy aimed at reducing perioperative complications in cancer surgery should include treatment of preoperative anaemia and an optimal fluid strategy, avoiding fluid overload and intraoperative use of colloids.

The 2021 re-emergence of yellow fever in non-human primates in the state of Rio Grande do Sul (RS), southernmost Brazil, resulted in the death of many howler monkeys (genus Alouatta) and led the state to declare a Public Health Emergency of State Importance, despite no human cases reported. In this study, near-complete genomes of yellow fever virus (YFV) recovered from the outbreak were sequenced and examined aiming at a better understanding of the phylogenetic relationships and the spatio-temporal dynamics of the virus distribution. Our results suggest that the most likely sequence of events involved the reintroduction of YFV from the state of São Paulo to RS through the states of Paraná and Santa Catarina, by the end of 2020. These findings reinforce the role of genomic surveillance in determining the pathways of distribution of the virus and in providing references for the implementation of preventive measures for populations in high risk areas.

Chagas disease, also known as American Trypanosomiasis, is caused by the protozoan . It is occurring in Americas, including USA and Canada, and Europe and its current treatment involves the use of two drugs as follows: benznidazole (BNZ) and nifurtimox, which present high toxicity and low efficacy during the chronic phase of the disease, thus promoting the search for more effective therapeutic alternatives. Amongst them xylan, a bioactive polysaccharide, extracted from corn cob. Ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy (FITR), Raman spectroscopy, energy-dispersive X-ray spectroscopy (EDS), scanning electron microscopy, atomic force microscopy, plasma optical emission spectroscopy (ICP-OES), dynamic light scattering (DLS) have been used to characterize the silver-xylan nanoparticles (NX). Their cytotoxicity was evaluated with 3-bromo(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) test. MTT and flow cytometry were used to ascertain the anti- activity. UV-Vis spectroscopy gave plasmon resonance ranging between 400 and 450 nm while FITC and Raman spectroscopy proved nano interface functionalized with xylan. ICP-OES data showed NX with xylan (81%) and silver (19%). EDS showed NX consisting of carbon (59.4%), oxygen (26.2%) and silver (4.8%) main elements. Spherical NX of 55 nm average size has been depicted with SEM and AFM, while DLS showed 102 ± 1.7 nm NX. The NX displayed negligible cytotoxicity (2000 µg/mL). NX (100 µg/mL) was more effective, regardless of experiment time, in affecting the ability of parasites to reduce MTT than BZN (100 µg/mL). In addition, NX (100 µg/mL) induced death of 95% of parasites by necrosis. This is the first time silver nanoparticles are presented as an anti- agent and the data point to the potential application of NX to new preclinical studies in vitro and in vivo.

Oxamniquine resistance evolved in the human blood fluke (Schistosoma monsoni) in Brazil in the 1970s. We crossed parental parasites differing -500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-f unction mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both 5. monsoni and 5. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.