Miracle-dz/UniFAR-FTUs huggingface dataset:
The neuronal oxygen‐sensing pathway controls postnatal vascularization of the murine brain

The contribution of neurons to growth and refinement of the microvasculature during postnatal brain development is only partially understood. Tissue hypoxia is the physiologic stimulus for angiogenesis by enhancing angiogenic mediators partly through activation of hypoxia‐inducible factors (HIFs). Hence, we investigated the HIF oxygen‐sensing pathway in postmitotic neurons for physiologic angiogenesis in the murine forebrain during postnatal development by using mice lacking the HIF suppressing enzyme prolyl‐4‐hydroxylase domain (PHD)2 and/or HIF‐1/2α in postmitotic neurons. Perinatal activation or inactivation of the HIF pathway in neurons inversely modulated brain vascularization, including endothelial cell number and proliferation, density of total and perfused microvessels, and vascular branching. Accordingly, several angiogenesis‐related genes were up‐regulated in vivo and in primary neurons derived from PHD2‐deficient mice. Among them, only VEGF and adrenomedullin (Adm) promoted angiogenic sprouting of brain endothelial cells. VEGF and Adm additively enhanced endothelial sprouting through activation of multiple pathways. PHD2 deficiency in neurons caused HIF‐α stabilization and increased VEGF mRNA levels not only in neurons but unexpectedly also in astrocytes, suggesting a new mechanism of neuron‐to‐astrocyte signaling. Collectively, our results identify the PHD‐HIF pathway in neurons as an important determinant for vascularization of the brain during postnatal development. —Nasyrov, E. , Nolan, K. A. , Wenger, R. H. , Marti, H. H. , Kunze, R. The neuronal oxygen‐sensing pathway controls postnatal vascularization of the murine brain. FASEB J. 33, 12812–12824 (2019). www.fasebj. org
Which Comes First in Contrast-Induced Nephropathy? Inflammation or Thrombus Formation?

We read with interest the study entitled “Can Thrombus Burden Predict Contrast Induced Nephropathy in Patients with ST-Segment Elevation Myocardial Infarction? ”. Contrast-induced nephropathy (CIN) is an important complication of cardiovascular interventions with an incidence of approximately 0.6% to 20% after procedures. Direct cytotoxicity to renal tubular cells, increased oxidative stress, increased blood, and renal tubular viscosity are some of the proposed causes of CIN. The study reported a relationship between thrombus burden and CIN. The authors state that a large thrombus burden can result in a high level of reactive oxygen radicals and lipid peroxidation, and this is the main reason for the association between thrombus burden and CIN. We partially agree but we would like to express our opinion about these results. Firstly, myocardial infarction is a complex acute event resulting in the activation of both the thrombotic and the inflammatory pathways. Initially, plaque rupture can occur with activation of the inflammatory pathway. Then, platelet activation, cytokines, and reactive oxygen radicals are triggered. This process adversely affects myocyte viability. In this context, the question is “Which comes first? Inflammation or thrombus formation? ”. We think that there is an association between thrombus burden and CIN. But the reason is not that high thrombus burden results with cytokine activation. It is because some patients (eg, those with diabetes mellitus or active inflammation as well as the aged) have an excessive cytokine response. In these patients, acute myocardial infarction results in a high thrombus burden and increased risk of CIN. We think that the relationship between thrombus burden and CIN also involves inflammatory pathway activation.
In vitro and in vivo evaluation of 3D bioprinted small-diameter vasculature with smooth muscle and endothelium

The ability to fabricate perfusable, small-diameter vasculature is a foundational step toward generating human tissues/organs for clinical applications. Currently, it is highly challenging to generate vasculature integrated with smooth muscle and endothelium that replicates the complexity and functionality of natural vessels. Here, a novel method for directly printing self-standing, small-diameter vasculature with smooth muscle and endothelium is presented through combining tailored mussel-inspired bioink and unique ‘fugitive-migration’ tactics, and its effectiveness and advantages over other methods (i.e. traditional alginate/calcium hydrogel, post-perfusion of endothelial cells) are demonstrated. The biologically inspired, catechol-functionalized, gelatin methacrylate (GelMA/C) undergoes rapid oxidative crosslinking in situ to form an elastic hydrogel, which can be engineered with controllable mechanical strength, high cell/tissue adhesion, and excellent bio-functionalization. The results demonstrate the bioprinted vascular construct possessed numerous favorable, biomimetic characteristics such as proper biomechanics, higher tissue affinity, vascularized tissue manufacturing ability, beneficial perfusability and permeability, excellent vasculoactivity, and in vivo autonomous connection (∼2 weeks) as well as vascular remodeling (∼6 weeks). The advanced achievements in creating biomimetic, functional vasculature illustrate significant potential toward generating a complicated vascularized tissue/organ for clinical transplantation.
Synthesis and Characterization of FITC Labelled Ruthenium Dendrimer as a Prospective Anticancer Drug

Metallodendrimers—dendrimers with included metals—are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case of using a dendrimer with a porphyrin core. In previous papers, we showed the promising anticancer effects of carbosilane ruthenium dendrimers. The present paper is devoted to studying biocompatibility and the cytotoxic effect on normal and cancer cells of carbosilane ruthenium dendrimers labelled with fluorescent probe fluorescein isothiocyanate (FITC). The addition of fluorescent probe allowed tracking the metallodendrimer in both normal and cancer cells. It was found that carbosilane ruthenium dendrimer labelled with FITC in concentration up to 10 µmol/L was more cytotoxic for cancer cells than for normal cells. Thus, FITC labelled carbosilane ruthenium dendrimer is a good candidate for diagnostic imaging and studying anticancer effects of metallodendrimers in cancer therapy.
A modern mold room: Meshing 3D surface scanning, digital design, and 3D printing with bolus fabrication

Abstract Purpose This case series represents an initial experience with implementing 3‐dimensional (3D) surface scanning, digital design, and 3D printing for bolus fabrication for patients with complex surface anatomy where traditional approaches are challenging. Methods and Materials For 10 patients requiring bolus in regions with complex contours, bolus was designed digitally from 3D surface scanning data or computed tomography (CT) images using either a treatment planning system or mesh editing software. Boluses were printed using a fused deposition modeling printer with polylactic acid. Quality assurance tests were performed for each printed bolus to verify density and shape. Results For 9 of 10 patients, digitally designed boluses were used for treatment with no issues. In 1 case, the bolus was not used because dosimetric requirements were met without the bolus. QA tests revealed that the bulk density was within 3% of the reference value for 9 of 12 prints, and with more judicious selection of print settings this could be increased. For these 9 prints, density uniformity was as good as or better than our traditional sheet bolus material. The average shape error of the pieces was less than 0.5 mm, and no issues with fit or comfort were encountered during use. Conclusions This study demonstrates that new technologies such as 3D surface scanning, digital design and 3D printing can be safely and effectively used to modernize bolus fabrication.
Role of AIP56 disulphide bond and its reduction by cytosolic redox systems for efficient intoxication

Apoptosis‐inducing protein of 56 kDa (AIP56) is a major virulence factor of Photobacterium damselae subsp. piscicida, a gram‐negative pathogen that infects warm water fish species worldwide and causes serious economic losses in aquacultures. AIP56 is a single‐chain AB toxin composed by two domains connected by an unstructured linker peptide flanked by two cysteine residues that form a disulphide bond. The A domain comprises a zinc‐metalloprotease moiety that cleaves the NF‐kB p65, and the B domain is involved in binding and internalisation of the toxin into susceptible cells. Previous experiments suggested that disruption of AIP56 disulphide bond partially compromised toxicity, but conclusive evidences supporting the importance of that bond in intoxication were lacking. Here, we show that although the disulphide bond of AIP56 is dispensable for receptor recognition, endocytosis, and membrane interaction, it needs to be intact for efficient translocation of the toxin into the cytosol. We also show that the host cell thioredoxin reductase‐thioredoxin system is involved in AIP56 intoxication by reducing the disulphide bond of the toxin at the cytosol. The present study contributes to a better understanding of the molecular mechanisms operating during AIP56 intoxication and reveals common features shared with other AB toxins.
Depicting the Non-Covalent Interaction of Whey Proteins with Galangin or Genistein Using the Multi-Spectroscopic Techniques and Molecular Docking

The non-covalent interactions between a commercial whey protein isolate (WPI) and two bioactive polyphenols galangin and genistein were studied at pH 6.8 via the multi-spectroscopic assays and molecular docking. When forming these WPI-polyphenol complexes, whey proteins had changed secondary structures while hydrophobic interaction was the major driving force. Detergent sodium dodecyl sulfate destroyed the hydrophobic interaction and thus decreased apparent binding constants of the WPI-polyphenol interactions. Urea led to hydrogen-bonds breakage and protein unfolding, and therefore increased apparent binding constants. Based on the measured apparent thermodynamic parameters like ΔH, ΔS, ΔG, and donor-acceptor distance, galangin with more planar stereochemical structure and random B-ring rotation showed higher affinity for WPI than genistein with location isomerism and twisted stereochemical structure. The molecular docking results disclosed that β-lactoglobulin of higher average hydrophobicity had better affinity for the two polyphenols than α-lactalbumin of lower average hydrophobicity while β-lactoglobulin possessed very similar binding sites to the two polyphenols. It is concluded that polyphenols might have different non-covalent interactions with food proteins, depending on the crucial polyphenol structures and protein hydrophobicity.
Metabonomics on Candida albicans indicate the excessive H3K56ac is involved in the antifungal activity of Shikonin

ABSTRACT Development of antifungal agents with novel mechanism and low toxicity are essential due to the prevalence of the infectious diseases caused by Candida albicans. The current study employed a new research method, which combined the ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry, to investigate the intrinsic mechanism of Shikonin (SK) against C. albicans. The levels of 27 metabolites, which mainly involved in histone deacetylation, amino acid synthesis, lipid synthesis, nitrogen metabolism, tricarboxylic acid cycle, oxidative stress and glycolysis, were remarkably changed upon SK treatment. Specially, the down-regulation of nicotinamide (NAM) upon SK treatment indicated the suppression of the deacetylation of the histone H3 on lysine 56 residue (H3K56). Further experiment confirmed that the level of H3K56 acetylation (H3K56ac) was dramatically increased upon SK treatment which was mediated by HST3, the gene encoding the H3K56 deacetylase (Hst3p). Our results demonstrated that SK is the first natural compound reported to execute antifungal activity directly via boosting H3K56ac mediated by HST3. Importantly, this finding shed new light on the mechanisms to relieve the side effects or reverse the drug tolerance, as well as the development of agents for antifungal therapies.
An exploratory investigation of geographic disparities of stroke prevalence in Florida using circular and flexible spatial scan statistics

Background Stroke is a major public health concern due to the morbidity and mortality associated with it. Identifying geographic areas with high stroke prevalence is important for informing public health interventions. Therefore, the objective of this study was to investigate geographic disparities and identify geographic hotspots of stroke prevalence in Florida. Materials and methods County-level stroke prevalence data for 2013 were obtained from the Florida Department of Health’s Behavioral Risk Factor Surveillance System (BRFSS). Geographic clusters of stroke prevalence were investigated using the Kulldorff’s circular spatial scan statistics (CSSS) and Tango’s flexible spatial scan statistics (FSSS) under Poisson model assumption. Exact McNemar’s test was used to compare the proportion of cluster counties identified by each of the two methods. Both Cohen’s Kappa and bias adjusted Kappa were computed to assess the level of agreement between CSSS and FSSS methods of cluster detection. Goodness-of-fit of the models were compared using Cluster Information Criterion. Identified clusters and selected stroke risk factors were mapped. Results Overall, 3.7% of adults in Florida reported that they had been told by a healthcare professional that they had suffered a stroke. Both CSSS and FSSS methods identified significant high prevalence stroke spatial clusters. However, clusters identified using CSSS tended to be larger than those identified using FSSS. The FSSS had a better fit than the CSSS. Most of the identified clusters are explainable by the prevalence distributions of the known risk factors assessed. Conclusions Geographic disparities of stroke risk exists in Florida with some counties having significant hotspots of high stroke prevalence. This information is important in guiding future research and control efforts to address the problem. Kulldorff’s CSSS and Tango’s FSSS are complementary to each other and should be used together to provide a more complete picture of the distributions of spatial clusters of health outcomes.
A Silicon Resonant Accelerometer Embedded in An Isolation Frame with Stress Relief Anchor

Bias thermal sensitivity is a significant performance parameter of a silicon resonant accelerometer (SRA) and is normally used to evaluate the degree of engineering practicability. Theoretical analysis demonstrates that temperature-induced stress is the dominant factor that determines the bias temperature drift of the custom-designed SRA. To solve this issue, this paper presents an SRA embedded in an isolation frame with stress insensitive anchor that prevents the resonant beams suffering from the thermal stress along the sense axis and thus improving the bias stability. Moreover, a high sensitivity device is achieved by integrating the vibrating beams with the comb fingers without conventional additional mass design. The experimental results show that the nominal resonant frequency of the SRA is around 93 kHz with the sensitivity and nonlinearity of 223.7 Hz/g and 5.1‰. The thermal sensitivities of the two resonant beams are −27.6 ppm/°C and −28.8 ppm/°C, respectively, which can be considered as the results owing to temperature change of the Young’s modulus without the thermal stress effect. The bias thermal sensitivity and the stability (1σ) after compensation are tested to be approximately 0.7 mg/°C and 1 mg over the temperature range from −40 °C to 60 °C with ±80 g measurement range.
Biochemical pathway for the biosynthesis of the CuA center in bacterial cytochrome c oxidase

The di‐copper center CuA is an essential metal cofactor in cytochrome oxidase (Cox) of mitochondria and many prokaryotes, mediating one‐electron transfer from cytochrome c to the site for oxygen reduction. CuA is located in subunit II (CoxB) of Cox and protrudes into the periplasm of Gram‐negative bacteria or the mitochondrial intermembrane space. How the two copper ions are brought together to build CoxB·CuA is the subject of this review. It had been known that the reductase TlpA and the metallochaperones ScoI and PcuC are required for CuA formation in bacteria, but the mechanism of copper transfer has emerged only recently for the Bradyrhizobium diazoefficiens system. It consists of the following steps: (a) TlpA keeps the active site cysteine pair of CoxB in its dithiol state as a prerequisite for metal insertion; (b) ScoI·Cu2+ rapidly forms a transient complex with apo‐CoxB; (c) PcuC, loaded with Cu1+ and Cu2+, dissociates this complex to CoxB·Cu2+, and a second PcuC·Cu1+·Cu2+ transfers Cu1+ to CoxB·Cu2+, yielding mature CoxB·CuA. Variants of this pathway might exist in other bacteria or mitochondria.
Improved Sparse Signal Reconstruction based on Approximate Hyperbolic Tangent Function with Smoothed l 0 Norm

In this paper, reconstruction algorithm for compressive sensing is based on smoothed l0 norm. The smoothed function sequence is introduced into the SL0 algorithm to approximate the l0 norm, and the minimization problem of l0 norm is transformed into the optimization problem of smoothed function.This paper has proposed a reconstruction algorithm with a modified Newton direction (ONSL0 algorithm) which is based on an optimized projection direction in l0 norm.The numerical simulation results show that the ONSL0 algorithm is better than both the SL0 algorithm and the OSL0 algorithm at the peak signal-to-noise ratio and relative error.
Cytosolic aggregates in presence of non‐translocated proteins perturb endoplasmic reticulum structure and dynamics

Presence of cytosolic protein aggregates and membrane damage are two common attributes of neurodegenerative diseases. These aggregates delay degradation of non‐translocated protein precursors leading to their persistence and accumulation in the cytosol. Here, we find that cells with intracellular protein aggregates (of cytosolic prion protein or huntingtin) destabilize the endoplasmic reticulum (ER) morphology and dynamics when non‐translocated protein load is high. This affects trafficking of proteins out from the ER, relative distribution of the rough and smooth ER and three‐way junctions that are essential for the structural integrity of the membrane network. The changes in ER membranes may be due to high aggregation tendency of the ER structural proteins—reticulons, and altered distribution of those associated with the three‐way ER junctions—Lunapark. Reticulon4 is seen to be enriched in the aggregate fractions in presence of non‐translocated protein precursors. This could be mitigated by improving signal sequence efficiencies of the proteins targeted to the ER. These were observed using PrP variants and the seven‐pass transmembrane protein (CRFR1) with different signal sequences that led to diverse translocation efficiencies. This identifies a previously unappreciated consequence of cytosolic aggregates on non‐translocated precursor proteins—their persistent presence affects ER morphology and dynamics. This may be one of the ways in which cytosolic aggregates can affect endomembranes during neurodegenerative disease.
Simvastatin Possesses Antitumor and Differentiation‐Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt‐related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin‐induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25‐dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation‐promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297‐310, 2020
Comparison of Machine Learning Techniques for Prediction of Hospitalization in Heart Failure Patients

The present study aims to compare the performance of eight Machine Learning Techniques (MLTs) in the prediction of hospitalization among patients with heart failure, using data from the Gestione Integrata dello Scompenso Cardiaco (GISC) study. The GISC project is an ongoing study that takes place in the region of Puglia, Southern Italy. Patients with a diagnosis of heart failure are enrolled in a long-term assistance program that includes the adoption of an online platform for data sharing between general practitioners and cardiologists working in hospitals and community health districts. Logistic regression, generalized linear model net (GLMN), classification and regression tree, random forest, adaboost, logitboost, support vector machine, and neural networks were applied to evaluate the feasibility of such techniques in predicting hospitalization of 380 patients enrolled in the GISC study, using data about demographic characteristics, medical history, and clinical characteristics of each patient. The MLTs were compared both without and with missing data imputation. Overall, models trained without missing data imputation showed higher predictive performances. The GLMN showed better performance in predicting hospitalization than the other MLTs, with an average accuracy, positive predictive value and negative predictive value of 81.2%, 87.5%, and 75%, respectively. Present findings suggest that MLTs may represent a promising opportunity to predict hospital admission of heart failure patients by exploiting health care information generated by the contact of such patients with the health care system.