Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance

We have previously shown significant pathology in the heart and kidney of murine hematopoietic-acute radiation syndrome (H-ARS) survivors of 8.7–9.0 Gy total-body irradiation (TBI). The goal of this study was to determine temporal relationships in the development of vasculopathy and the progression of renal and cardiovascular delayed effects of acute radiation exposure (DEARE) at TBI doses less than 9 Gy and to elucidate the potential roles of senescence, inflammation and oxidative stress. Our results show significant loss of endothelial cells in coronary arteries by 4 months post-TBI (8.53 or 8.72 Gy of gamma radiation). This loss precedes renal dysfunction and interstitial fibrosis and progresses to abnormalities in the arterial media and adventitia and loss of coronary arterioles. Major differences in radiation-induced pathobiology exist between the heart and kidney in terms of vasculopathy progression and also in indices of inflammation, senescence and oxidative imbalance. The results of this work suggest a need for different medical countermeasures for multiple targets in different organs and at various times after acute radiation injury to prevent the progression of DEARE. Unthank, J. L, Ortiz, M. , Trivedi, H. , Pelus, L. M. , Sampson, C. H. , Sellamuthu, R. , Fisher, A. , Chua, H. L. , Plett, A. , Orschell, C. M. , Cohen, E. P. and Miller, S. J. Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance. Radiat. Res. 191, 383–397 (2019).
A roadmap for implementation of patient‐centered digital outcome measures in Parkinson's disease obtained using mobile health technologies

Obtaining reliable longitudinal information about everyday functioning from individuals with Parkinson's disease (PD) in natural environments is critical for clinical care and research. Despite advances in mobile health technologies, the implementation of digital outcome measures is hindered by a lack of consensus on the type and scope of measures, the most appropriate approach for data capture (eg, in clinic or at home), and the extraction of timely information that meets the needs of patients, clinicians, caregivers, and health care regulators. The Movement Disorder Society Task Force on Technology proposes the following objectives to facilitate the adoption of mobile health technologies: (1) identification of patient‐centered and clinically relevant digital outcomes; (2) selection criteria for device combinations that offer an acceptable benefit‐to‐burden ratio to patients and that deliver reliable, clinically relevant insights; (3) development of an accessible, scalable, and secure platform for data integration and data analytics; and (4) agreement on a pathway for approval by regulators, adoption into e‐health systems and implementation by health care organizations. We have developed a tentative roadmap that addresses these needs by providing the following deliverables: (1) results and interpretation of an online survey to define patient‐relevant endpoints, (2) agreement on the selection criteria for use of device combinations, (3) an example of an open‐source platform for integrating mobile health technology output, and (4) recommendations for assessing readiness for deployment of promising devices and algorithms suitable for regulatory approval. This concrete implementation guidance, harmonizing the collaborative endeavor among stakeholders, can improve assessments of individuals with PD, tailor symptomatic therapy, and enhance health care outcomes. © 2019 International Parkinson and Movement Disorder Society
Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction.

AIMS Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE-/- FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). METHODS AND RESULTS Compared with normo-ferremic ApoE-/- mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE-/- FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE-/- FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. CONCLUSION Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.
Changes in Endothelial Nitric Oxide Production in Systemic Vessels during Early Ontogenesis—A Key Mechanism for the Perinatal Adaptation of the Circulatory System

Nitric oxide (NO) produced in the wall of blood vessels is necessary for the regulation of vascular tone to ensure an adequate blood supply of organs and tissues. In this review, we present evidence that the functioning of endothelial NO-synthase (eNOS) changes considerably during postnatal maturation. Alterations in NO-ergic vasoregulation in early ontogeny vary between vascular beds and correlate with the functional reorganization of a particular organ. Importantly, the anticontractile effect of NO can be an important mechanism responsible for the protectively low blood pressure in the immature circulatory system. The activity of eNOS is regulated by a number of hormones, including thyroid hormones which are key regulators of the perinatal developmental processes. Maternal thyroid hormone deficiency suppresses the anticontractile effect of NO at perinatal age. Such alterations disturb perinatal cardiovascular homeostasis and lead to delayed occurring cardiovascular pathologies in adulthood. The newly discovered role of thyroid hormones may have broad implications in cardiovascular medicine, considering the extremely high prevalence of maternal hypothyroidism in human society.
The Neural Dynamics of Novel Scene Imagery

Retrieval of long-term episodic memories is characterized by synchronized neural activity between hippocampus and ventromedial prefrontal cortex (vmPFC), with additional evidence that vmPFC activity leads that of the hippocampus. It has been proposed that the mental generation of scene imagery is a crucial component of episodic memory processing. If this is the case, then a comparable interaction between the two brain regions should exist during the construction of novel scene imagery. To address this question, we leveraged the high temporal resolution of MEG to investigate the construction of novel mental imagery. We tasked male and female humans with imagining scenes and single isolated objects in response to one-word cues. We performed source-level power, coherence, and causality analyses to characterize the underlying interregional interactions. Both scene and object imagination resulted in theta power changes in the anterior hippocampus. However, higher theta coherence was observed between the hippocampus and vmPFC in the scene compared with the object condition. This interregional theta coherence also predicted whether imagined scenes were subsequently remembered. Dynamic causal modeling of this interaction revealed that vmPFC drove activity in hippocampus during novel scene construction. Additionally, theta power changes in the vmPFC preceded those observed in the hippocampus. These results constitute the first evidence in humans that episodic memory retrieval and scene imagination rely on similar vmPFC–hippocampus neural dynamics. Furthermore, they provide support for theories emphasizing similarities between both cognitive processes and perspectives that propose the vmPFC guides the construction of context-relevant representations in the hippocampus. SIGNIFICANCE STATEMENT Episodic memory retrieval is characterized by a dialog between hippocampus and ventromedial prefrontal cortex (vmPFC). It has been proposed that the mental generation of scene imagery is a crucial component of episodic memory processing. An ensuing prediction would be of a comparable interaction between the two brain regions during the construction of novel scene imagery. Here, we leveraged the high temporal resolution of MEG and combined it with a scene imagination task. We found that a hippocampal–vmPFC dialog existed and that it took the form of vmPFC driving the hippocampus. We conclude that episodic memory and scene imagination share fundamental neural dynamics and the process of constructing vivid, spatially coherent, contextually appropriate scene imagery is strongly modulated by vmPFC.
Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC Enhanced by Autologous Concentrated Bone Marrow Aspirate (BMAC) Allow for Stable Clinical and Functional Improvements at up to 9 Years Follow-Up: Results from a Randomized Controlled Study

The aims of the study were to evaluate long-term outcomes after autologous matrix-induced chondrogenesis (AMIC) in the treatment of focal chondral lesions and to assess the possible improvements given by the combination of this technique with bone marrow aspirate concentrate (BMAC). Twenty-four patients (age range 18–55 years) affected by focal knee chondral lesions were treated with standard AMIC or AMIC enhanced by BMAC (AMIC+). Pain (Visual Analogue Scale (VAS)) and functional scores (Lysholm, International Knee Documentation Committee (IKDC), Tegner, Knee injury and Osteoarthritis Outcome Score (KOOS)) were collected pre-operatively and then at 6, 12, 24, 60, and 100 months after treatment. Magnetic resonance imaging (MRI) evaluation was performed pre-operatively and at 6, 12, and 24 months follow-ups. Patients treated with AMIC+ showed higher Lysholm scores (p = 0.015) and lower VAS (p = 0.011) in comparison with patients in the standard AMIC group at the 12 months follow-up. Both treatments allowed for functional and pain improvements with respect to pre-operative levels lasting up to 100 months. MRI revealed consistent cartilage repair at 24 months in both groups. This study shows that AMIC and AMIC+ are effective treatments for focal chondral lesions with beneficial effect lasting up to 9 years. AMIC+ allows for faster recovery from injury, and is thus more indicated for patients requiring a prompt return to activity. Level of evidence: II, randomized controlled trial in an explorative cohort.
Antiviral Activity of Uridine Derivatives of 2-Deoxy Sugars against Tick-Borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV) is a causative agent of tick-borne encephalitis (TBE), one of the most important human infections involving the central nervous system. Although effective vaccines are available on the market, they are recommended only in endemic areas. Despite many attempts, there are still no specific antiviral therapies for TBEV treatment. Previously, we synthesized a series of uridine derivatives of 2-deoxy sugars and proved that some compounds show antiviral activity against viruses from the Flaviviridae and Orthomyxoviridae families targeting the late steps of the N-glycosylation process, affecting the maturation of viral proteins. In this study, we evaluated a series of uridine derivatives of 2-deoxy sugars for their antiviral properties against two strains of the tick-borne encephalitis virus; the highly virulent TBEV strain Hypr and the less virulent strain Neudoerfl. Four compounds (2, 4, 10, and 11) showed significant anti-TBEV activity with IC50 values ranging from 1.4 to 10.2 µM and low cytotoxicity. The obtained results indicate that glycosylation inhibitors, which may interact with glycosylated membrane TBEV E and prM proteins, might be promising candidates for future antiviral therapies against TBEV.
Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma.

PURPOSE Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.
Glycosylation of the viral attachment protein of avian coronavirus is essential for host cell and receptor binding

Avian coronaviruses, including infectious bronchitis virus (IBV), are important respiratory pathogens of poultry. The heavily glycosylated IBV spike protein is responsible for binding to host tissues. Glycosylation sites in the spike protein are highly conserved across viral genotypes, suggesting an important role for this modification in the virus life cycle. Here, we analyzed the N-glycosylation of the receptor-binding domain (RBD) of IBV strain M41 spike protein and assessed the role of this modification in host receptor binding. Ten single Asn–to–Ala substitutions at the predicted N-glycosylation sites of the M41–RBD were evaluated along with two control Val–to–Ala substitutions. CD analysis revealed that the secondary structure of all variants was retained compared with the unmodified M41–RBD construct. Six of the 10 glycosylation variants lost binding to chicken trachea tissue and an ELISA-presented α2,3-linked sialic acid oligosaccharide ligand. LC/MSE glycomics analysis revealed that glycosylation sites have specific proportions of N-glycan subtypes. Overall, the glycosylation patterns of most variant RBDs were highly similar to those of the unmodified M41–RBD construct. In silico docking experiments with the recently published cryo-EM structure of the M41 IBV spike protein and our glycosylation results revealed a potential ligand receptor site that is ringed by four glycosylation sites that dramatically impact ligand binding. Combined with the results of previous array studies, the glycosylation and mutational analyses presented here suggest a unique glycosylation-dependent binding modality for the M41 spike protein.
NMDA Receptor Model of Antipsychotic Drug-Induced Hypofrontality

Schizophrenia is a chronic mental disease, affecting around 1% of the general population. Schizophrenia is characterized by productive, negative, affective, and disorganization symptoms, and cognitive deficits. Cognitive deficits prevail in most of the schizophrenia patients and are one of the most disabling symptoms. They usually occur before the acute episode of the disease and tend to become chronic with no satisfactory treatment from antipsychotic drugs. Because of their early manifestation in patients’ lives, cognitive deficits are suggested to be the primary symptom of schizophrenia. The pathogenesis of cognitive deficits in schizophrenia is not fully understood. They are linked with hypofrontality, which is a decrease in blood flow and glucose metabolism in the prefrontal lobe of schizophrenia-suffering patients. Hypofrontality is linked with disturbances of the corticolimbothalamic circuit, important for cognition and memory in humans. The circuit consists of a group of neuroanatomic structures and hypothetically any disturbance in them may result in cognitive deficits. We present a translational preclinical model of understanding how antipsychotic medication may decrease the N-methyl-D-aspartic acid (NMDA) receptors’ activity and produce dysfunctions in the corticolimbothalamic circuit and hypofrontality. From several pharmacological experiments on rats, including mainly our own recent findings, we collected data that suggest that antipsychotic medication may maintain and escalate hypofrontality in schizophrenia, decreasing NMDA receptor activity in the corticolimbothalamic circuit in the human brain. We discuss our findings within the literature of the subject.
Application of Inner Radiation Baffles in the Bridgman Process for Flattening the Temperature Profile and Controlling the Columnar Grain Structure of Directionally Solidified Ni-Based Superalloys

The technique of flattening the temperature profile and controlling the formation of both the dendritic microstructure and grain structure in the directional solidification of nickel-based superalloy casting, using the novel inner radiation baffles (IRBs) in the Bridgman process, is presented in this paper. These baffles matched to the shape of mold and were placed horizontally along its height at various distances from the casting base. The plate castings of CMSX-4 superalloy were fabricated without and with the use of IRBs, withdrawing the mold at the rate of 6 mm/min from the heating to the cooling area of the industrial Bridgman furnace. Thermal analysis of the directional solidification of castings was carried out using the ProCAST software for a process where the various designs of the radiation baffle were applied. The results of the solidification conditions, the shape of liquidus and solidus isotherms, and grain structure obtained for the IRBs were compared with those reached for the standard ring-shaped (AERB) or perfectly adjusted (PARB) radiation baffles. The use of IRB resulted in flattening of the temperature distribution and decrease of the curvature of liquidus and solidus isotherms, as well as an increase of temperature gradient and cooling rate, compared with the process where AERB was only used. Consequently, primary dendrite arm spacing (PDAS) reached similar values across the width of casting and equaled to approximately 370 μm, reducing its average value by 26%, compared with the standard process. The change in predicted axial temperature gradient in casting was not found when thermophysical properties of molybdenum IRBs were used. The increase in graphite IRBs number in mold from seven to 14 caused the reduction of inhomogeneity of axial temperature gradient along the casting height.
Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size

Abstract Background Acute rejection (AR) is one of the most frequent complications after kidney transplantation (KT). Scientific evidence reports that some single-nucleotide polymorphisms (SNPs) located in genes involved in the immune response and in the pharmacokinetics and pharmacodynamics of immunosuppressive drugs are associated with rejection in renal transplant patients. The aim of this study was to evaluate some SNPs located in six genes: interleukin-10 (IL-10), tumor necrosis factor (TNF), adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), uridine diphosphate glucuronosyltransferase family 1 member A9 (UGT1A9), inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2. Methods We enrolled cases with at least one AR after KT and two groups of controls: patients without any AR after KT and healthy blood donors. Genetic analysis on DNA was performed. The heterozygosity (HET) was determined and the Hardy-Weinberg equilibrium (HWE) test was performed for each SNP. The sample size was calculated using the QUANTO program and the genetic associations were calculated using the SAS program (SAS Institute Inc., Cary, NC, USA). Results In our previous preliminary study (sample size was not reached for cases), the results showed that patients with the C allele in the SNP rs1045642 and the A allele in the SNP rs2032582 of the ABCB1 gene had more frequent AR. In contrast, with the achievement of sample size, the trend of the previous data was not confirmed. Conclusions Our study highlights a fundamental aspect of scientific research that is generally presumed, i.e. the sample size of groups enrolled for a scientific study. We believe that our study will make a significant contribution to the scientific community in the discussion of the importance of the analysis and the achievement of sample size to evaluate the associations between SNPs and the studied event.
Acellular Fish Skin Grafts for Management of Split Thickness Donor Sites and Partial Thickness Burns: A Case Series.

METHODS Ten patients having split-thickness skin grafting for burn injury were treated with the fish skin xenografts. RESULTS There were no adverse reactions noted on the use of the fish skin grafts. No patient had any reaction to the fish skin and there was a zero incidence of infection. The handling of the fish skin was excellent, a robust and pliable xenograft that was easy to apply.The quality of donor site healing was judged to be good in all cases. Both the analgesic effect noted and the relatively short average times until 100% re-epithelialization are promising. We also illustrate two cases where the dressing was used to treat superficial burns.