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The release of extracellular vesicles (EVs) in cell cultures as well as their molecular cargo can be influenced by cell culture conditions such as the presence of foetal bovine serum (FBS). Although several studies have evaluated the effect of removing FBS‐derived EVs by ultracentrifugation (UC), less is known about the influence of FBS heat inactivation (HI) on the cell‐derived EVs. To assess this, three protocols based on different combinations of EV depletion by UC and HI were evaluated, including FBS ultracentrifuged but not heat inactivated (no‐HI FBS), FBS heat inactivated before EV depletion (HI‐before EV‐depl FBS), and FBS heat inactivated after EV depletion (HI‐after EV‐depl FBS). We isolated large (L‐EVs) and small EVs (S‐EVs) from FBS treated in the three different ways, and we found that the S‐EV pellet from HI‐after EV‐depl FBS was larger than the S‐EV pellet from no‐HI FBS and HI‐before EV‐depl FBS. Transmission electron microscopy, protein quantification, and particle number evaluation showed that HI‐after EV‐depl significantly increased the protein amount of S‐EVs but had no significant effect on L‐EVs. Consequently, the protein quantity of S‐EVs isolated from three cell lines cultured in media supplemented with HI‐after EV‐depl FBS was significantly increased. Quantitative mass spectrometry analysis of FBS‐derived S‐EVs showed that the EV protein content was different when FBS was HI after EV depletion compared to EVs isolated from no‐HI FBS and HI‐before EV‐depl FBS. Moreover, we show that several quantified proteins could be ascribed to human origin, thus demonstrating that FBS bovine proteins can mistakenly be attributed to human cell‐derived EVs. We conclude that HI of FBS performed after EV depletion results in changes in the proteome, with molecules that co‐isolate with EVs and can contaminate EVs when used in subsequent cell cultures. Our recommendation is, therefore, to always perform HI of FBS prior to EV depletion.

Three-dimensional (3D) bioprinting is one of the most promising methodologies that are currently in development for the replacement of animal experiments. Bioprinting and most alternative technologies rely on animal-derived materials, which compromises the intent of animal welfare and results in the generation of chimeric systems of limited value. The current study therefore presents the first bioprinted liver model that is entirely void of animal-derived constituents. Initially, HuH-7 cells underwent adaptation to a chemically defined medium (CDM). The adapted cells exhibited high survival rates (85–92%) after cryopreservation in chemically defined freezing media, comparable to those preserved in standard medium (86–92%). Xeno-free bioink for 3D bioprinting yielded liver models with high relative cell viability (97–101%), akin to a Matrigel-based liver model (83–102%) after 15 days of culture. The established xeno-free model was used for toxicity testing of a marine biotoxin, okadaic acid (OA). In 2D culture, OA toxicity was virtually identical for cells cultured under standard conditions and in CDM. In the xeno-free bioprinted liver model, 3-fold higher concentrations of OA than in the respective monolayer culture were needed to induce cytotoxicity. In conclusion, this study describes for the first time the development of a xeno-free 3D bioprinted liver model and its applicability for research purposes.

This research explores the complex relationship between creativity and cognitive processes during the design process, focusing on the mechanisms that stimulate conceptual expansion and shifts in understanding how creative insights emerge. The study involved 25 participants who employed the think-aloud protocol to tackle a specific design task. Linkographic entropies derived from verbal data collected during design sessions were employed to identify critical moves (CM) and their corresponding design decisions. The CM networks were analysed and coded using the Function-Behaviour-Structure (FBS) ontology to classify design actions. Furthermore, semantic analysis was conducted to categorise the types of design transformations as either conceptual expansions or conceptual shifts. The findings reveal that conceptual shifts are achieved solely through Synthesis, while conceptual expansions serve as the foundational elements for these shifts. Cognitive actions-specifically reformulations and evaluations-were found to facilitate conceptual expansions and contribute to conceptual shifts at various levels. The effectiveness and type of these conceptual transformations are influenced by the distance between the knowledge sets used during cognitive actions. Formulation and Analysis do not contribute to fostering conceptual transformations. The study contributes to a deeper understanding of the cognitive processes underlying design creativity, providing insights for both design education and professional practice.

Background Properly understanding the health information of people with type 2 diabetes mellitus (T2DM) is the basis for better risk factor management, which also positively affects their quality of life. The aim of this study was to investigate diabetes health literacy (HL), self-efficacy, and self-care behaviors associated with glycemic control among older adults with T2DM in northern Thai communities. Methods A cross-sectional study was conducted among 414 older adults over the age of 60 diagnosed with T2DM. The study was conducted in Phayao Province from January to May 2022. Simple random sampling of the patient list for the Java Health Center Information System program was used. Questionnaires were used to collect data on diabetes HL, self-efficacy, and self-care behaviors. Blood samples were tested for estimated glomerular filtration rate (eGFR) and glycemic controls, such as fasting blood sugar (FBS) and glycated hemoglobin (HbA1c). Results The mean age of participants was 67.1 years. FBS (mean ± SD = 108.5 ± 29.5 mg/dL) and HbA1c (mean ± SD = 6.6 ± 1.2%) levels were found to be abnormal in 50.5% (≥ 126 mg/dL) and 17.4% (≥ 6.5%) of the subjects, respectively. There was a strong correlation between HL and self-efficacy (r = 0.78), HL and self-care behaviors (r = 0.76), and self-efficacy and self-care behaviors (r = 0.84). The eGFR was significantly correlated with diabetes HL (r = 0.23), self-efficacy (r = 0.14), self-care behaviors (r = 0.16), and HbA1c (r = -0.16) scores. Linear regression after adjusting for sex, age, education, DM duration, smoking, and drinking alcohol showed that FBS level was inversely associated with diabetes HL (Beta = -0.21, R 2  = 11.0%), self-efficacy (Beta = -0.43, R 2  = 22.2%), and self-care behavior (Beta = -0.35, R 2  = 17.8%), whereas HbA1C level was negatively associated with diabetes HL (Beta = -0.52, R 2  = 23.8%), self-efficacy (Beta = -0.39, R 2  = 19.1%), and self-care behavior (Beta = -0.42, R 2  = 20.7%). Conclusion Diabetes HL was related to self-efficacy and self-care behaviors in elderly T2DM patients and was shown to influence their health, including glycemic control. These findings suggest that implementing HL programs to build competence in self-efficacy expectations is important for contributing to improvements in diabetes preventive care behaviors and HbA1c control.

Accumulation of glycogen in the kidney and liver is the main feature of Fanconi–Bickel Syndrome (FBS), a rare disorder of carbohydrate metabolism inherited in an autosomal recessive manner due to SLC2A2 gene mutations. Missense, nonsense, frame-shift (fs), in-frame indels, splice site, and compound heterozygous variants have all been identified in SLC2A2 gene of FBS cases. Approximately 144 FBS cases with 70 different SLC2A2 gene variants have been reported so far. SLC2A2 encodes for glucose transporter 2 (GLUT2) a low affinity facilitative transporter of glucose mainly expressed in tissues playing important roles in glucose homeostasis, such as renal tubular cells, enterocytes, pancreatic β-cells, hepatocytes and discrete regions of the brain. Dysfunctional mutations and decreased GLUT2 expression leads to dysglycaemia (fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, and rarely diabetes mellitus), hepatomegaly, galactose intolerance, rickets, and poor growth. The molecular mechanisms of dysglycaemia in FBS are still not clearly understood. In this review, we discuss the physiological roles of GLUT2 and the pathophysiology of mutants, highlight all of the previously reported SLC2A2 mutations associated with dysglycaemia, and review the potential molecular mechanisms leading to dysglycaemia and diabetes mellitus in FBS patients.

This research explores the relationship between creativity and cognitive actions in a design process that cause conceptual expansion and shift to understand how creative insights develop. The research was conducted with 25 participants using the think-aloud protocol who were given a design problem to solve. Linkographic entropies were obtained from the verbal data of design sessions to determine critical moves (CM) and their associated design decisions. CM networks were then coded using Function-Behaviour-Structure (FBS) ontology to determine design actions, and semantic analysis was used to determine the design transformation types. The results showed that conceptual shift is only achieved through Synthesis, while conceptual expansions serve as a base for conceptual shifts. Cognitive actions such as reformulations and evaluations were found to cause conceptual expansions and contribute to conceptual shifts at different levels. The distance between knowledge sets used during cognitive actions influences the effectiveness and types of conceptual transformations. The research concludes that Formulation and Analysis do not contribute to conceptual transformations. The research provides insights into the cognitive processes underlying design creativity and can inform design education and practice.

Mesenchymal stem cell (MSC) culturing for cell therapies needs a step forward to be routinely used in clinical settings. Main concerns regard the use of animal origin reagents, in particular supplementing the culture medium with FBS. Lately, Human Platelet Lysate (HPL) has been proposed as animal-free alternative, described as an excellent supplement for culturing MSCs. The aim of this systematic review was to analyze the current literature on the effect of HPL and FBS on ASCs and BMSCs. The primary outcome was the proliferation rate of cells cultured with FBS and HPL. Differences in terms of doubling time (DT) and population doubling (PD) were evaluated by meta-analysis, subgrouping data according to the cell type. A total of 35 articles were included. BMSCs and ASCs were used in 65.7% (23) and 28.6% (10) studies, respectively. Only two studies included both cell types. Overall, 22 studies were eligible for the meta-analysis. Among them, 9 articles described ASCs and 13 BMSCs. The results showed that BMSCs and ASCs cultured with 10% HPL and 5% HPL have lower DT and higher PD compared to cells cultured with 10% FBS. A possible correlation between the DT decrease and the application of at least 3 freeze/thaw cycles to induce platelet lysis was found. Additionally, HPL increased VEGF secretion and maintained the immuno-modulatory abilities for both cell types. The clarification reported here of the higher efficiency of HPL compared to FBS can help the transition of the scientific community towards clinical-related procedures. Graphical Abstract 1. The meta-analysis shows that HPL induces a population doubling increase and a doubling time decrease of both ASCs and BMSCs compared to FBS. 2. When at least 3 freeze/thaw cycles are applied to induce platelet lysis, the doubling time of HPL-cultured cells is lower than FBS-cultured cells (Created with BioRender.com).

Background Intra-articular injection of mesenchymal stem cells (MSCs) is efficacious in osteoarthritis therapy. A direct comparison of the response of the synovial joint to intra-articular injection of autologous versus allogeneic MSCs has not been performed. The objective of this study was to assess the clinical response to repeated intra-articular injection of allogeneic versus autologous MSCs prepared in a way to minimize xeno-contaminants in a large animal model. Methods Intra-articular injections of bone marrow-derived, culture-expanded MSCs to a forelimb metacarpophalangeal joint were performed at week 0 and week 4 (six autologous; six autologous with xeno-contamination; six allogeneic). In the week following each injection, clinical and synovial cytology evaluations were performed. Results Following the first intra-articular injection, there were no differences in clinical parameters over time. Following the second intra-articular injection, there was a significant adverse response of the joint to allogeneic MSCs and autologous MSCs with xeno-contamination with elevated synovial total nucleated cell counts. There was also significantly increased pain from joints injected with autologous MSCs with xeno-contamination. Conclusions Repeated intra-articular injection of allogeneic MSCs results in an adverse clinical response, suggesting there is immune recognition of allogeneic MSCs upon a second exposure.

Failure mode and effect analysis (FMEA) model is a technique used to evaluate the risk. This paper aimed to propose a new FMEA model combining technique for order of preference by similarity to ideal solution (TOPSIS) and belief structure to overcome the shortcomings of the traditional index of FMEA. In this paper, the fuzzy belief TOPSIS method is combined with FMEA to introduce a belief structure FMEA to describe the expert knowledge by a number of linguists as a grammatical phenomenon. Moreover, the weights of components in FMEA index can be different from each other. Therefore, the flexibility of assigning weight to each factor in this method is more compatible to the real decision-making situation. In other word, TOPSIS method is applied to determine the preference of alternatives versus risk criteria. Using linguistic terms in the fuzzy belief approach, the risk factors described a more meaningful value and decision-makers’ judgment is assigned with belief degrees through evaluation of factors. Finally, a numerical case study about the preference of cause failures of steel production process is provided to illustrate the process of proposed method, and then result and discussion is performed for each case.