Miracle-dz/UniFAR-FTUs huggingface dataset:
Wall Shear Stress Predicts Media Degeneration and Biomechanical Changes in Thoracic Aorta

Objectives: In thoracic aortic aneurysm (TAA) of the ascending aorta (AA), AA is progressively dilating due to the weakening of the aortic wall. Predicting and preventing aortic dissections and ruptures in TAA continues to be challenging, and more accurate assessment of the AA dilatation, identification of high-risk patients, and timing of repair surgery are required. We investigated whether wall shear stress (WSS) predicts pathological and biomechanical changes in the aortic wall in TAA. Methods: The study included 12 patients with bicuspid (BAV) and 20 patients with the tricuspid aortic valve (TAV). 4D flow magnetic resonance imaging (MRI) was performed a day before aortic replacement surgery. Biomechanical and histological parameters, including assessing of wall strength, media degeneration, elastin, and cell content were analyzed from the resected AA samples. Results: WSSs were greater in the outer curves of the AA compared to the inner curves in all TAA patients. WSSs correlated with media degeneration of the aortic wall (ρ = -0.48, p < 0.01), elastin content (ρ = 0.47, p < 0.01), and aortic wall strength (ρ = -0.49, p = 0.029). Subsequently, the media of the outer curves was thinner, more rigid, and tolerated lower failure strains. Failure values were shown to correlate with smooth muscle cell (SMC) density (ρ = -0.45, p < 0.02), and indicated the more MYH10+ SMCs the lower the strength of the aortic wall structure. More macrophages were detected in patients with severe media degeneration and the areas with lower WSSs. Conclusion: The findings indicate that MRI-derived WSS predicts pathological and biomechanical changes in the aortic wall in patients with TAA and could be used for identification of high-risk patients.
Paranodal Axoglial Junctions, an Essential Component in Axonal Homeostasis

In vertebrates, a high density of voltage-gated Na+ channel at nodes of Ranvier and of voltage-gated K+ channel at juxtaparanodes is necessary for rapid propagation of action potential, that is, for saltatory conduction in myelinated axons. Myelin loops attach to the axonal membrane and form paranodal axoglial junctions (PNJs) at paranodes adjacent to nodes of Ranvier. There is growing evidence that the PNJs contribute to axonal homeostasis in addition to their roles as lateral fences that restrict the location of nodal axolemmal proteins for effective saltatory conduction. Perturbations of PNJs, as in specific PNJ protein knockouts as well as in myelin lipid deficient mice, result in internodal axonal alterations, even if their internodal myelin is preserved. Here we review studies showing that PNJs play crucial roles in the myelinated axonal homeostasis. The present evidence points to two functions in particular: 1) PNJs facilitate axonal transport of membranous organelles as well as cytoskeletal proteins; and 2) they regulate the axonal distribution of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) in cerebellar Purkinje axons. Myelinated axonal homeostasis depends among others on the state of PNJs, and consequently, a better understanding of this dependency may contribute to the clarification of CNS disease mechanisms and the development of novel therapies.
Stress and Diet Quality Among Ecuadorian Adults During the COVID-19 Pandemic. A Cross-Sectional Study

Background Stress has been associated with food habits. Stress changes eating patterns and the salience and consumption of hyperpalatable foods. During the lock-down due to the COVID-19 pandemic, stress was very common. Objective We investigated the association between stress and diet quality in Ecuadorian adults during the COVID-19 pandemic. Design A cross-sectional study. Setting Data was collected using a self-administered online survey. Stress was measured using the Perceived Stress Scale (PSS-14), and diet quality was evaluated using the Global Diet Index (GDI). A linear regression model with restrictive cubic splines was used to investigate the association between stress and diet quality. Participants Participants were recruited by convenience sampling, including a total of 2602 individuals. Most participants were female (68.57%) and had university education (78.52%), with a median age of 25 (IQR: 25, 37). Results Stress was reported by 26.06% of participants. The majority of individuals (75.79%) reported having a diet that needed changes or an unhealthy diet. Independently from biological sex, age, level of education, people/room ratio, economic allowance, and expenses for food, stress was statistically significantly associated with diet quality (p = 0.035). The association between stress and diet quality was inverse and non-linear; higher stress levels were associated with poorer diet quality. The consumption of palatable foods was not statistically significant associated with stress. Conclusions Stress is associated with poorer diet quality. Public health measures to improve the mental health and lifestyle of the population are needed during the lock-down of the pandemic.
Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.
Holder Pasteurization: Comparison of Water-Bath and Dry-Tempering Devices

Background Human milk (HM) for premature infants is frequently Holder pasteurized (heated at 62.5 ± 0.5°C for 30 min) despite its detrimental effects on heat-sensitive milk components. This tolerated compromise ensures HM's microbial safety while less detrimental methods like short-time HM treatments (HTST) are still being evaluated. Dry-tempering devices (DT-HoP) were recently introduced in clinical practice due to hygienic concerns about water-based Holder pasteurizers (WB-HoP). Evidence on the impact of such dry-tempering devices on HM quality is lacking. The aim of this study was to compare protein retention rates after DT-HoP, WB-HoP and HTST. Methods We colorimetrically determined alkaline phosphatase activity (ALP), concentrations of secretory immunoglobulin A (sIgA), and lactoferrin (LF) before and after DT-HoP, WB-HoP and HTST. Results ALP was below the detection limit after HoP, but retained 52.8 ± 13% activity after HTST (p < 0.01). Secretory IgA (WB-HoP = 73.2 ± 13.5% vs. DT-HoP = 57 ± 14%, p = 0.0018) and LF retention (WB-HoP=47 ± 40% vs. DT-HoP=25 ± 8%, p = 0.07) differed between the two HoP modes. Again, retention was better maintained after HTST compared to HoP (80.4 ± 23% sIgA and 70 ± 42% LF concentration, all p < 0.01). Conclusion Dry-tempering milk lowers even further the quality of HM when performing HoP compared to water-bath pasteurization, while HTST warrants continued evaluation for clinical application.
Designed for Innovation: The Structure of IPR Regimes and the Evolution of Information Technologies

The large legal and economic literature on intellectual property rights (IPRs) presents contradictory arguments on the eAEciency of the legal regime to promote innovation and technical change in information technologies. On one extreme, limited protection of intellectual assets enables rivals to imitate innovations with a little e ort and to remove part of the revenues of inventors. A lack of intellectual property regimes would decrease the propensity of rms to invest in R&D and in the long run may slow down the development of technologies and hamper innovation. On the other extreme, over-protective regimes provide strong monopoly rights and dominance over broad shares of the technology and/or for long periods. Patentholders are able to preempt other rms from introducing new products that fall into the scope of valid patents. Therefore, patens enable the introduction of technological advances by other rms only in non-infringing features of patented products and, hence, reduce product di erentiation. The dimensions of the legal regime that are studied in this paper are the length and minimal inventive step of patents. We aim at identifying the desirable structure of the regime in which maximal technological progress is achieved. We construct a simulation model of a market of heterogeneous users and rms to analyze the evolution of information technologies. The dynamics of innovation is described as a series of sequential, cumulative advances in the technical qualities of features. The paper identi es the relationships between di erent degrees of patent protection and market dynamics (in terms of technical quality, di usion, rms' behaviour and market organization). The minimal inventive step and the duration are the policy parameters whose in uence on innovation is assessed by the model. The results of the model suggest that in the current patent regime the legal provisions are to a large extent over-protective and may result in a slowdown in the advance of software technologies. The policy implications of the model go beyond assessing the e ects of extending the patent regime to include information technologies in its scope. The analysis provides a wide-ranging instrument that assists policy makers in evaluating the impact of changes in the legal framework on the evolution of technologies. JEL Classi cation: L15, L51, O34.
Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients

Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5–15 ng mL−1. Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h−1 (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg−1 d−1 (q12h), respectively. Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.
A Preliminary in vitro and in vivo Evaluation of the Effect and Action Mechanism of 17-AAG Combined With Azoles Against Azole-Resistant Candida spp.

Invasive candidiasis is the primary reason for the increased cases of mortality in a medical environment. The resistance spectra of Candida species to antifungal drugs have gradually expanded. Particularly, the resistance spectra of Candida auris are the most prominent. Hsp90 plays a protective role in the stress response of fungi and facilitates their virulence. In contrast, Hsp90 inhibitors can improve the resistance of fungi to antifungal drugs by regulating the heat resistance of Hsp90, which destroys the integrity of the fungal cell walls. Hsp90 inhibitors thus offer a great potential to reduce or address fungal drug resistance. The drugs tested for the resistance include itraconazole, voriconazole, posaconazole, fluconazole, and 17-AAG. A total of 20 clinical strains of Candida were investigated. The broth microdilution checkerboard technique, as adapted from the CLSI M27-A4 method, was applied in this study. We found that 17-AAG alone exerted limited antifungal activity against all tested strains. The MIC range of 17-AAG was 8 to >32 μg/ml. A synergy was observed among 17-AAG and itraconazole, voriconazole, and posaconazole against 10 (50%), 7 (35%), and 13 (65%) of all isolates, respectively. Moreover, the synergy between 17-AAG and fluconazole was observed against 5 (50%) strains of azole-resistant Candida. However, no antagonism was recorded overall. Our result adequately verifies the influence of 17-AAG on the formation of Candida spp. biofilm. Moreover, we determined that with the use of rhodamine 6G to detect drug efflux and that of dihydrorhodamine-123 to detect intracellular reactive oxygen species (ROS), treatment with 17-AAG combined with azole drugs could inhibit the efflux pump of fungi and promote the accumulation of ROS in the fungal cells, thereby inducing fungal cell apoptosis. Thus, the mechanism of 17-AAG combined with azoles can kill fungi. Our results thus provide a new idea to further explore drugs against drug-resistant Candida spp.
Neutrophil Survival Signaling During Francisella tularensis Infection

Neutrophils are the most abundant and shortest-lived leukocytes in humans and tight regulation of neutrophil turnover via constitutive apoptosis is essential for control of infection and resolution of inflammation. Accordingly, aberrant neutrophil turnover is hallmark of many disease states. We have shown in previous work that the intracellular bacterial pathogen Francisella tularensis markedly prolongs human neutrophil lifespan. This is achieved, in part, by changes in neutrophil gene expression. Still unknown is the contribution of major neutrophil pro-survival signaling cascades to this process. The objective of this study was to interrogate the contributions of ERK and p38 MAP kinase, Class I phosphoinositide 3-kinases (PI3K), AKT, and NF-κB to neutrophil survival in our system. We demonstrate that both ERK2 and p38α were activated in F. tularensis-infected neutrophils, but only p38α MAPK was required for delayed apoptosis and the rate of cell death in the absence of infection was unchanged. Apoptosis of both infected and uninfected neutrophils was markedly accelerated by the pan-PI3K inhibitor LY2094002, but AKT phosphorylation was not induced, and neutrophil death was not enhanced by AKT inhibitors. In addition, isoform specific and selective inhibitors revealed a unique role for PI3Kα in neutrophil survival after infection, whereas only simultaneous inhibition of PI3Kα and PI3kδ accelerated death of the uninfected controls. Finally, we show that inhibition of NF-κB triggered rapid death of neutrophil after infection. Thus, we defined roles for p38α, PI3Kα and NF-κB delayed apoptosis of F. tularensis-infected cells and advanced understanding of Class IA PI3K isoform activity in human neutrophil survival.
High-Accuracy Oral Squamous Cell Carcinoma Auxiliary Diagnosis System Based on EfficientNet

It is important to diagnose the grade of oral squamous cell carcinoma (OSCC), but the current evaluation of the biopsy slide still mainly depends on the manual operation of pathologists. The workload of manual evaluation is large, and the results are greatly affected by the subjectivity of the pathologists. In recent years, with the development and application of deep learning, automatic evaluation of biopsy slides is gradually being applied to medical diagnoses, and it has shown good results. Therefore, a new OSCC auxiliary diagnostic system was proposed to automatically and accurately evaluate the patients’ tissue slides. This is the first study that compared the effects of different resolutions on the results. The OSCC tissue slides from The Cancer Genome Atlas (TCGA, n=697) and our independent datasets (n=337) were used for model training and verification. In the test dataset of tiles, the accuracy was 93.1% at 20x resolution (n=306,134), which was higher than that at 10x (n=154,148, accuracy=90.9%) and at 40x (n=890,681, accuracy=89.3%). The accuracy of the new system based on EfficientNet, which was used to evaluate the tumor grade of the biopsy slide, reached 98.1% [95% confidence interval (CI): 97.1% to 99.1%], and the area under the receiver operating characteristic curve (AUROC) reached 0.998 (95%CI: 0.995 to 1.000) in the TCGA dataset. When verifying the model on the independent image dataset, the accuracy still reached 91.4% (95% CI: 88.4% to 94.4%, at 20x) and the AUROC reached 0.992 (95%CI: 0.982 to 1.000). It may benefit oral pathologists by reducing certain repetitive and time-consuming tasks, improving the efficiency of diagnosis, and facilitating the further development of computational histopathology.
Structural New Data for Mitochondrial Peroxiredoxin From Trypanosoma cruzi Show High Similarity With Human Peroxiredoxin 3: Repositioning Thiostrepton as Antichagasic Drug

Trypanosoma cruzi, the causal agent of Chagas disease, has peroxiredoxins (PRXs) expressed in all stages of the parasite and whose function is to detoxify oxidizing agents, such as reactive oxygen species (ROS). These proteins are central for the survival and replication of the parasite and have been proposed as virulence factors. Because of their importance, they have also been considered as possible therapeutic targets, although there is no specific drug against them. One of them, the mitochondrial PRX (TcMPX), is important in the detoxification of ROS in this organelle and has a role in the infectivity of T. cruzi. However, their structural characteristics are unknown, and possible inhibitors have not been proposed. The aim was to describe in detail some structural characteristics of TcMPX and compare it with several PRXs to find possible similarities and repositioning the antibiotic Thiostrepton as a potential inhibitor molecule. It was found that, in addition to the characteristic active site of a 2-cys PRX, this protein has a possible transmembrane motif and motifs involved in resistance to hyper oxidation. The homology model suggests a high structural similarity with human PRX3. This similarity was corroborated by cross-recognition using an anti-human PRX antibody. In addition, molecular docking showed that Thiostrepton, a potent inhibitor of human PRX3, could bind to TcMPX and affect its function. Our results show that Thiostrepton reduces the proliferation of T. cruzi epimastigotes, cell-derived trypomastigotes, and blood trypomastigotes with low cytotoxicity on Vero cells. We also demonstrated a synergic effect of Thriostepton and Beznidazol. The convenience of seeking treatment alternatives against T. cruzi by repositioning compounds as Thiostrepton is discussed.
Enzymatic Active Release of Violacein Present in Nanostructured Lipid Carrier by Lipase Encapsulated in 3D-Bioprinted Chitosan-Hydroxypropyl Methylcellulose Matrix With Anticancer Activity

Violacein (Viol) is a bacterial purple water-insoluble pigment synthesized by Chromobacterium violaceum and other microorganisms that display many beneficial therapeutic properties including anticancer activity. Viol was produced, purified in our laboratory, and encapsulated in a nanostructured lipid carrier (NLC). The NLC is composed of the solid lipid myristyl myristate, an oily lipid mixture composed of capric and caprylic acids, and the surfactant poloxamer P188. Dormant lipase from Rhizomucor miehei was incorporated into the NLC-Viol to develop an active release system. The NLC particle size determined by dynamic light scattering brings around 150 nm particle size and ζ≈ −9.0 mV with or without lipase, but the incorporation of lipase increase the PdI from 0.241 to 0.319 (≈32%). For scaffold development, a 2.5 hydroxypropyl methylcellulose/chitosan ratio was obtained after optimization of a composite for extrusion in a 3D-bioprinter developed and constructed in our laboratory. Final Viol encapsulation efficiency in the printings was over 90%. Kinetic release of the biodye at pH = 7.4 from the mesh containing NLC-lipase showed roughly 20% Viol fast release than without the enzyme. However, both Viol kinetic releases displayed similar profiles at pH = 5.0, where the lipase is inactive. The kinetic release of Viol from the NLC-matrices was modeled and the best correlation was found with the Korsmeyer-Peppas model (R2 = 0.95) with n < 0.5 suggesting a Fickian release of Viol from the matrices. Scanning Electron Microscope (SEM) images of the NLC-meshes showed significant differences before and after Viol’s release. Also, the presence of lipase dramatically increased the gaps in the interchain mesh. XRD and Fourier Transform Infrared (FTIR) analyses of the NLC-meshes showed a decrease in the crystalline structure of the composites with the incorporation of the NLC, and the decrease of myristyl myristate in the mesh can be attributed to the lipase activity. TGA profiles of the NLC-meshes showed high thermal stability than the individual components. Cytotoxic studies in A549 and HCT-116 cancer cell lines revealed high anticancer activity of the matrix mediated by mucoadhesive chitosan, plus the biological synergistic activities of violacein and lipase.