Miracle-dz/UniFAR-FTUs huggingface dataset:
Towards Biohybrid Lung: Induced Pluripotent Stem Cell Derived Endothelial Cells as Clinically Relevant Cell Source for Biologization

In order to provide an alternative treatment option to lung transplantation for patients with end-stage lung disease, we aim for the development of an implantable biohybrid lung (BHL), based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. Complete hemocompatibility of all blood contacting surfaces is crucial for long-lasting BHL durability and can be achieved by their endothelialization. Autologous endothelial cells (ECs) would be the ideal cell source, but their limited proliferation potential excludes them for this purpose. As induced pluripotent stem cell-derived ECs enable the generation of a large number of ECs, we assessed and compared their capacity to form a viable and confluent monolayer on HFM, while indicating physiologic EC-specific anti-thrombogenic and anti-inflammatory properties. ECs were generated from three different human iPSC lines, and seeded onto fibronectin-coated poly-4-methyl-1-pentene (PMP) HFM. Following phenotypical characterization, ECs were analyzed for their thrombogenic and inflammatory behavior with or without TNFα induction, using FACS and qRT-PCR. Complementary, leukocyte- and platelet adhesion assays were carried out. The capacity of the iPSC-ECs to reendothelialize cell-free monolayer areas was assessed in a scratch assay. ECs sourced from umbilical cord blood (hCBECs) were used as control. iPSC-derived ECs formed confluent monolayers on the HFM and showed the typical EC-phenotype by expression of VE-cadherin and collagen-IV. A low protein and gene expression level of E-selectin and tissue factor was detected for all iPSC-ECs and the hCBECs, while a strong upregulation of these markers was noted upon stimulation with TNFα. This was in line with the physiological and strong induction of leukocyte adhesion detected after treatment with TNFα, iPSC-EC and hCBEC monolayers were capable of reducing thrombocyte adhesion and repopulating scratched areas. iPSCs offer the possibility to provide patient-specific ECs in abundant numbers needed to cover all blood contacting surfaces of the BHL with a viable, non-thrombogenic and non-inflammatory monolayer. iPSC-EC clones can differ in terms of their reendothelialization rate, and pro-inflammatory response. However, a less profound inflammatory response may even be advantageous for BHL application. With the proven ability of the seeded iPSC-ECs to reduce thrombocyte adhesion, we expect that thrombotic events that could lead to BHL occlusion can be avoided, and thus, justifies further studies on enabling BHL long-term application.
Barriers and Opportunities for Sustainable Hand Hygiene Interventions in Rural Liberian Hospitals

Hand hygiene is central to hospital infection control. During the 2014–2016 West Africa Ebola virus disease epidemic in Liberia, gaps in hand hygiene infrastructure and health worker training contributed to hospital-based Ebola transmission. Hand hygiene interventions were undertaken post-Ebola, but many improvements were not sustainable. This study characterizes barriers to, and facilitators of, hand hygiene in rural Liberian hospitals and evaluates readiness for sustainable, locally derived interventions to improve hand hygiene. Research enumerators collected data at all hospitals in Bong and Lofa counties, Liberia, in the period March–May 2020. Enumerators performed standardized spot checks of hand hygiene infrastructure and supplies, structured observations of hand hygiene behavior, and semi-structured key informant interviews for thematic analysis. During spot checks, hospital staff reported that handwashing container water was always available in 89% (n = 42) of hospital wards, piped running water in 23% (n = 11), and soap in 62% (n = 29). Enumerators observed 5% of wall-mounted hand sanitizer dispensers (n = 8) and 95% of pocket-size dispensers (n = 53) to be working. In interviews, hospital staff described willingness to purchase personal hand sanitizer dispensers when hospital-provided supplies were unavailable. Low-cost, sustainable interventions should address supply and infrastructure-related obstacles to hospital hand hygiene improvement.
Methanogenic Biodegradation of iso-Alkanes by Indigenous Microbes from Two Different Oil Sands Tailings Ponds

iso-Alkanes, a major fraction of the solvents used in bitumen extraction from oil sand ores, are slow to biodegrade in anaerobic tailings ponds. We investigated methanogenic biodegradation of iso-alkane mixtures comprising either three (2-methylbutane, 2-methylpentane, 3-methylpentane) or five (2-methylbutane, 2-methylpentane, 2-methylhexane, 2-methylheptane, 2-methyloctane) iso-alkanes representing paraffinic and naphtha solvents, respectively. Mature fine tailings (MFT) collected from two tailings ponds, having different residual solvents (paraffinic solvent in Canadian Natural Upgrading Limited (CNUL) and naphtha in Canadian Natural Resources Limited (CNRL)), were amended separately with the two mixtures and incubated in microcosms for ~1600 d. The indigenous microbes in CNUL MFT produced methane from the three-iso-alkane mixture after a lag of ~200 d, completely depleting 2-methylpentane while partially depleting 2-methylbutane and 3-methylpentane. CNRL MFT exhibited a similar degradation pattern for the three iso-alkanes after a lag phase of ~700 d, but required 1200 d before beginning to produce methane from the five-iso-alkane mixture, preferentially depleting components in the order of decreasing carbon chain length. Peptococcaceae members were key iso-alkane-degraders in both CNUL and CNRL MFT but were associated with different archaeal partners. Co-dominance of acetoclastic (Methanosaeta) and hydrogenotrophic (Methanolinea and Methanoregula) methanogens was observed in CNUL MFT during biodegradation of three-iso-alkanes whereas CNRL MFT was enriched in Methanoregula during biodegradation of three-iso-alkanes and in Methanosaeta with five-iso-alkanes. This study highlights the different responses of indigenous methanogenic microbial communities in different oil sands tailings ponds to iso-alkanes.
Assessment of Copper and Heavy Metals in Family-Run Vineyard Soils and Wines of Campania Region, South Italy

Copper-based phytosanitary treatments are widely employed in viticulture for combating the fungal diseases of European grape (Vitis vinifera L.). Herein we evaluated copper accumulation in the soil of a 50-year-old still productive vineyard in South Italy in comparison with samples taken from a ‘control’ area in which grapevines had never been cultivated, as well from an abandoned vineyard, now planted with cereals and forage crops, both close to the main area under investigation. Even though the heavy metal contents detected were not of concern for soils nor for wine, Cu accumulates in the soil in amounts significantly higher than the (grapevine free) control and remains at detectable concentrations also in abandoned vineyards where spraying activities had ceased about 20 years before this study. Despite the long Cu residence times in soil, the wine produced with grapes of the same vineyard showed Cu levels low enough to be safely used for human consumption, probably due to mechanisms of metal precipitation occurring during wine maturation, which are typically accompanied by sedimentation processes in artisanal production. However, this should not diminish the urgency of decreasing the copper usage as antifungal remedy in viticulture to prevent copper contamination of the agricultural soils.
High-Pressure Mechanistic Insight into Bioinorganic NO Chemistry

Pressure is one of the most important parameters controlling the kinetics of chemical reactions. The ability to combine high-pressure techniques with time-resolved spectroscopy has provided a powerful tool in the study of reaction mechanisms. This review is focused on the supporting role of high-pressure kinetic and spectroscopic methods in the exploration of nitric oxide bioinorganic chemistry. Nitric oxide and other reactive nitrogen species (RNS) are important biological mediators involved in both physiological and pathological processes. Understanding molecular mechanisms of their interactions with redox-active metal/non-metal centers in biological targets, such as cofactors, prosthetic groups, and proteins, is crucial for the improved therapy of various diseases. The present review is an attempt to demonstrate how the application of high-pressure kinetic and spectroscopic methods can add additional information, thus enabling the mechanistic interpretation of various NO bioinorganic reactions.
Treatment of Dyspareunia with Botulinum Neurotoxin Type A: Clinical Improvement and Influence of Patients’ Characteristics

The treatment of chronic pelvic pain (CPP) with botulinum neurotoxin type A (BoNT/A) has increased lately, but more studies assessing its effect are needed. This study aimed to evaluate the evolution of patients after BoNT/A infiltration and identify potential responders to treatment. Twenty-four women with CPP associated with dyspareunia were treated with 90 units of BoNT/A injected into their pelvic floor muscle (PFM). Clinical status and PFM activity were monitored in a previous visit (PV) and 12 and 24 weeks after the infiltration (W12, W24) by validated clinical questionnaires and surface electromyography (sEMG). The influence of patients’ characteristics on the reduction in pain at W12 and W24 was also assessed. After treatment, pain scores and the impact of symptoms on quality of life dropped significantly, sexual function improved and sEMG signal amplitude decreased on both sides of the PFM with no adverse events. Headaches and bilateral pelvic pain were risk factors for a smaller pain improvement at W24, while lower back pain was a protective factor. Apart from reporting a significant clinical improvement of patients with CPP associated with dyspareunia after BoNT/A infiltration, this study shows that clinical characteristics should be analyzed in detail to identify potential responders to treatment.
Does Sodium Intake Induce Systemic Inflammatory Response? A Systematic Review and Meta-Analysis of Randomized Studies in Humans

Experimental studies suggest that sodium induced inflammation might be another missing link leading to atherosclerosis. To test the hypothesis that high daily sodium intake induces systemic inflammatory response in humans, we performed a systematic review according to PRISMA guidelines of randomized controlled trials (RCTs) that examined the effect of high versus low sodium dose (HSD vs. LSD), as defined per study, on plasma circulating inflammatory biomarkers. Eight RCTs that examined CRP, TNF-a and IL-6 were found. Meta-analysis testing the change of each biomarker in HSD versus LSD was possible for CRP (n = 5 studies), TNF-a (n = 4 studies) and IL-6 (n = 4 studies). The pooled difference (95% confidence intervals) per biomarker was for: CRP values of 0.1(−0.3, 0.4) mg/L; TNF-a −0.7(−5.0, 3.6) pg/mL; IL-6 −1.1(−3.3 to 1.1) pg/mL. Importantly, there was inconsistency between RCTs regarding major population characteristics and the applied methodology, including a very wide range of LSD (460 to 6740 mg/day) and HSD (2800 to 7452 mg/day). Although our results suggest that the different levels of daily sodium intake are not associated with significant changes in the level of systemic inflammation in humans, this outcome may result from methodological issues. Based on these identified methodological issues we propose that future RCTs should focus on young healthy participants to avoid confounding effects of comorbidities, should have three instead of two arms (very low, “normal” and high) of daily sodium intake with more than 100 participants per arm, whereas an intervention duration of 14 days is adequate.
Fecal Supernatant from Adult with Autism Spectrum Disorder Alters Digestive Functions, Intestinal Epithelial Barrier, and Enteric Nervous System

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders defined by impaired social interactions and communication with repetitive behaviors, activities, or interests. Gastrointestinal (GI) disturbances and gut microbiota dysbiosis are frequently associated with ASD in childhood. However, it is not known whether microbiota dysbiosis in ASD patients also occurs in adulthood. Further, the consequences of altered gut microbiota on digestive functions and the enteric nervous system (ENS) remain unexplored. Therefore, we studied, in mice, the ability offecal supernatant (FS) from adult ASD patients to induce GI dysfunctions and ENS remodeling. First, the analyses of the fecal microbiota composition in adult ASD patients indicated a reduced α-diversity and increased abundance of three bacterial 16S rRNA gene amplicon sequence variants compared to healthy controls (HC). The transfer of FS from ASD patients (FS–ASD) to mice decreased colonic barrier permeability by 29% and 58% compared to FS–HC for paracellular and transcellular permeability, respectively. These effects are associated with the reduced expression of the tight junction proteins JAM-A, ZO-2, cingulin, and proinflammatory cytokines TNFα and IL1β. In addition, the expression of glial and neuronal molecules was reduced by FS–ASD as compared to FS-HC in particular for those involved in neuronal connectivity (βIII-tubulin and synapsin decreased by 31% and 67%, respectively). Our data suggest that changes in microbiota composition in ASD may contribute to GI alterations, and in part, via ENS remodeling.
Impact of Idarucizumab and Andexanet Alfa on DOAC Plasma Concentration and ClotPro® Clotting Time: An Ex Vivo Spiking Study in A Cohort of Trauma Patients

Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell’s viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p < 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p < 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p < 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers’ blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.
An Exchange Mechanism for the Magnetic Behavior of Er3+ Complexes

We study the magnetic properties of the erbium based compounds, Na9[Er(W5O18)2] and [(Pc)Er{Pc{N(C4H9)2}8}]·/−, in the framework of an effective spin exchange model involving delocalized electrons occupying molecular orbitals. The calculations successfully reproduce the experimental data available in the literature for the magnetic spectrum, magnetization and molar susceptibility in dc and ac fields. Owing to their similar molecular geometry, the compounds’ magnetic behaviors are interpreted in terms of the same set of active orbitals and thus the same effective spin coupling scheme. For all three complexes, the model predicts a prompt change in the ground state from a Kramer’s doublet at zero fields to a fully polarized quartet one brought about by the action of an external magnetic field without Zeeman splitting. This alteration is attributed to the enhancement of the effect of orbital interactions over the spin exchange as the magnitude of the external magnetic field increases.
Clinical Findings in SMR Neurofeedback Protocol Training in Women with Fibromyalgia Syndrome

Fibromyalgia is related to central sensitization syndrome (CSS) and is associated with chronic pain and a decrease in general health. The aim of this study was to explore how changes in brain patterns of female fibromyalgia patients are shaped by neurofeedback therapy and how it affects pain perception and general health. A quasi-experimental study with pre- and post-tests was carried out with 37 female fibromyalgia patients referred by the Pain Unit of the National Health Service of Spain. The method involved applying a sensorimotor rhythm (SMR) protocol to monitor changes in brain waves under different conditions, taking pre-/post-test measurements of perceived pain, general health and the impact on fibromyalgia. Measures included the Fibromyalgia Impact Questionnaire Revised (FIQR), the Visual Analogue Scale (VAS), the General Health Questionnaire (GHQ-28) and EEG (SMR, theta waves). During therapy, the SMR/theta wave ratio increased significantly and after application of therapy, significant results were observed for the FIQR, VAS and GHQ-28. In conclusion, neurofeedback therapy increases the SMR/theta wave ratio in fibromyalgia, helping to maintain a balance between brain functions. This is associated with the activation of inhibitory processes, which is related to the perceived improvement of pain in fibromyalgia patients.
Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)—an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO—control, AIA—untreated adjuvant-induced arthritis, AIA-BIL—adjuvant-induced arthritis administrated UCB, CO-BIL—control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund’s adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.
Heat Shock Proteins: Connectors between Heart and Kidney

Over the development of eukaryotic cells, intrinsic mechanisms have been developed in order to provide the ability to defend against aggressive agents. In this sense, a group of proteins plays a crucial role in controlling the production of several proteins, guaranteeing cell survival. The heat shock proteins (HSPs), are a family of proteins that have been linked to different cellular functions, being activated under conditions of cellular stress, not only imposed by thermal variation but also toxins, radiation, infectious agents, hypoxia, etc. Regarding pathological situations as seen in cardiorenal syndrome (CRS), HSPs have been shown to be important mediators involved in the control of gene transcription and intracellular signaling, in addition to be an important connector with the immune system. CRS is classified as acute or chronic and according to the first organ to suffer the injury, which can be the heart (CRS type 1 and type 2), kidneys (CRS type 3 and 4) or both (CRS type 5). In all types of CRS, the immune system, redox balance, mitochondrial dysfunction, and tissue remodeling have been the subject of numerous studies in the literature in order to elucidate mechanisms and propose new therapeutic strategies. In this sense, HSPs have been targeted by researchers as important connectors between kidney and heart. Thus, the present review has a focus to present the state of the art regarding the role of HSPs in the pathophysiology of cardiac and renal alterations, as well their role in the kidney–heart axis.
Quantification of the Immune Content in Neuroblastoma: Deep Learning and Topological Data Analysis in Digital Pathology

We introduce here a novel machine learning (ML) framework to address the issue of the quantitative assessment of the immune content in neuroblastoma (NB) specimens. First, the EUNet, a U-Net with an EfficientNet encoder, is trained to detect lymphocytes on tissue digital slides stained with the CD3 T-cell marker. The training set consists of 3782 images extracted from an original collection of 54 whole slide images (WSIs), manually annotated for a total of 73,751 lymphocytes. Resampling strategies, data augmentation, and transfer learning approaches are adopted to warrant reproducibility and to reduce the risk of overfitting and selection bias. Topological data analysis (TDA) is then used to define activation maps from different layers of the neural network at different stages of the training process, described by persistence diagrams (PD) and Betti curves. TDA is further integrated with the uniform manifold approximation and projection (UMAP) dimensionality reduction and the hierarchical density-based spatial clustering of applications with noise (HDBSCAN) algorithm for clustering, by the deep features, the relevant subgroups and structures, across different levels of the neural network. Finally, the recent TwoNN approach is leveraged to study the variation of the intrinsic dimensionality of the U-Net model. As the main task, the proposed pipeline is employed to evaluate the density of lymphocytes over the whole tissue area of the WSIs. The model achieves good results with mean absolute error 3.1 on test set, showing significant agreement between densities estimated by our EUNet model and by trained pathologists, thus indicating the potentialities of a promising new strategy in the quantification of the immune content in NB specimens. Moreover, the UMAP algorithm unveiled interesting patterns compatible with pathological characteristics, also highlighting novel insights into the dynamics of the intrinsic dataset dimensionality at different stages of the training process. All the experiments were run on the Microsoft Azure cloud platform.