Miracle-dz/UniFAR-FTUs huggingface dataset:
Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1&agr; (Hypoxia-Inducible Factor-1&agr;) Pathway in Endothelial Cells

Objective— Calcific aortic valve (AV) disease, characterized by AV sclerosis and calcification, is a major cause of death in the aging population; however, there are no effective medical therapies other than valve replacement. AV calcification preferentially occurs on the fibrosa side, exposed to disturbed flow (d-flow), whereas the ventricularis side exposed to predominantly stable flow remains protected by unclear mechanisms. Here, we tested the role of novel flow-sensitive UBE2C (ubiquitin E2 ligase C) and microRNA-483-3p (miR-483) in flow-dependent AV endothelial function and AV calcification. Approach and Results— Human AV endothelial cells and fresh porcine AV leaflets were exposed to stable flow or d-flow. We found that UBE2C was upregulated by d-flow in human AV endothelial cells in the miR-483–dependent manner. UBE2C mediated OS-induced endothelial inflammation and endothelial-mesenchymal transition by increasing the HIF-1&agr; (hypoxia-inducible factor-1&agr;) level. UBE2C increased HIF-1&agr; by ubiquitinating and degrading its upstream regulator pVHL (von Hippel-Lindau protein). These in vitro findings were corroborated by immunostaining studies using diseased human AV leaflets. In addition, we found that reduction of miR-483 by d-flow led to increased UBE2C expression in human AV endothelial cells. The miR-483 mimic protected against endothelial inflammation and endothelial-mesenchymal transition in human AV endothelial cells and calcification of porcine AV leaflets by downregulating UBE2C. Moreover, treatment with the HIF-1&agr; inhibitor (PX478) significantly reduced porcine AV calcification in static and d-flow conditions. Conclusions— These results suggest that miR-483 and UBE2C and pVHL are novel flow-sensitive anti- and pro-calcific AV disease molecules, respectively, that regulate the HIF-1&agr; pathway in AV. The miR-483 mimic and HIF-1&agr; pathway inhibitors may serve as potential therapeutics of calcific AV disease.
Motion Artifacts and Correction in Multipulse High-Frame Rate Contrast-Enhanced Ultrasound

High-frame-rate (HFR) ultrasound (US) imaging and contrast-enhanced US (CEUS) are often implemented using multipulse transmissions, to enhance image quality. Multipulse approaches, however, suffer from degradation in the presence of motion, especially when coherent compounding and CEUS are combined. In this paper, we investigate this effect on the intensity of HFR CEUS in deep tissue imaging using simulations and in vivo contrast echocardiography (CE). The simulation results show that the motion artifact is much higher when the flow is in an axial direction than a lateral direction. Using a pulse repetition frequency suitable for cardiac imaging, a motion of 35 cm/s can cause as much as 28.5 dB decrease in image intensity, where compounding can contribute up to 18.7 dB of intensity decrease (11 angles). These motion effects are also demonstrated for in vivo cardiac HFR CE, where the large velocities of both the myocardium and the blood are present. Intensity reductions of 10.4 dB are readily visible in the chamber. Finally, we demonstrate how performing motion–correction before pulse inversion compounding greatly reduces such motion artifact and improve image signal-to-noise ratio and contrast.
Advancing Research on LGBTQ Microaggressions: A Psychometric Scoping Review of Measures

ABSTRACT Understanding the nature and consequences of LGBTQ microaggressions is critical to fostering equity and wellbeing among sexual and gender minorities. Yet little guidance is available for researchers seeking psychometrically robust measures of subtle LGBTQ slights, invalidations, and insults. To address this gap, we conducted a scoping review of multi-item quantitative measures that included at least one question addressing LGBTQ microaggressions. This article reports the study characteristics and psychometric properties of 27 original measures we identified and their subsequent adaptations. The article concludes with an assessment of strengths and limitations of LGBTQ microaggression measurement, highlighting aspects of measurement innovation on which future researchers can build. As microaggressions remain a powerful and underexplored mechanism of sexual and gender minority oppression, this review will help to both advance methodological quality in this critical research area and enhance our understanding of how microaggressions manifest in the lives of LGBTQ individuals.
Process Optimization and Upscaling of Spray-Dried Drug-Amino acid Co-Amorphous Formulations

The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 22 full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (Fatom, from 0.5 to 1.4 kg/h) and outlet temperature (Tout, from 55 to 75 °C) were chosen as the critical process parameters. The obtained amorphization, glass transition temperature, bulk density, yield, and particle size distribution were chosen as the critical quality attributes. In general, the model showed low Fatom and high Tout to be beneficial for the desired product characteristics (a co-amorphous formulation with a low bulk density, high yield, and small particle size). In addition, only a low Fatom and high Tout led to the desired complete co-amorphization, while a minor residual crystallinity was observed with the other combinations of Fatom and Tout. Finally, upscaling to a pilot scale spray dryer was carried out based on the DoE results; however, the drying gas flow rate and the feed flow rate were adjusted to account for the different drying chamber geometries. An increased likelihood to achieve complete amorphization, because of the extended drying chamber, and hence an increased residence time of the droplets in the drying gas, was found in the pilot scale, confirming the feasibility of upscaling spray drying as a production technique for co-amorphous systems.
Materials for the Spine: Anatomy, Problems, and Solutions

Disc degeneration affects 12% to 35% of a given population, based on genetics, age, gender, and other environmental factors, and usually occurs in the lumbar spine due to heavier loads and more strenuous motions. Degeneration of the extracellular matrix (ECM) within reduces mechanical integrity, shock absorption, and swelling capabilities of the intervertebral disc. When severe enough, the disc can bulge and eventually herniate, leading to pressure build up on the spinal cord. This can cause immense lower back pain in individuals, leading to total medical costs exceeding $100 billion. Current treatment options include both invasive and noninvasive methods, with spinal fusion surgery and total disc replacement (TDR) being the most common invasive procedures. Although these treatments cause pain relief for the majority of patients, multiple challenges arise for each. Therefore, newer tissue engineering methods are being researched to solve the ever-growing problem. This review spans the anatomy of the spine, with an emphasis on the functions and biological aspects of the intervertebral discs, as well as the problems, associated solutions, and future research in the field.
Kinetic and molecular dynamics study of inhibition and transglycosylation in Hypocrea jecorina family 3 β-glucosidases

β-Glucosidases enhance enzymatic biomass conversion by relieving cellobiose inhibition of endoglucanases and cellobiohydrolases. However, the susceptibility of these enzymes to inhibition and transglycosylation at high glucose or cellobiose concentrations severely limits their activity and, consequently, the overall efficiency of enzyme mixtures. We determined the impact of these two processes on the hydrolytic activity of the industrially relevant family 3 β-glucosidases from Hypocrea jecorina, HjCel3A and HjCel3B, and investigated the underlying molecular mechanisms through kinetic studies, binding free energy calculations, and molecular dynamics (MD) simulations. HjCel3B had a 7-fold higher specificity for cellobiose than HjCel3A but greater tendency for glucose inhibition. Energy decomposition analysis indicated that cellobiose has relatively weak electrostatic interactions with binding site residues, allowing it to be easily displaced by glucose and free to inhibit other hydrolytic enzymes. HjCel3A is, thus, preferable as an industrial β-glucosidase despite its lower activity caused by transglycosylation. This competing pathway to hydrolysis arises from binding of glucose or cellobiose at the product site after formation of the glycosyl-enzyme intermediate. MD simulations revealed that binding is facilitated by hydrophobic interactions with Trp-37, Phe-260, and Tyr-443. Targeting these aromatic residues for mutation to reduce substrate affinity at the product site would therefore potentially mitigate transglycosidic activity. Engineering improved variants of HjCel3A and other structurally similar β-glucosidases would have a significant economic effect on enzymatic biomass conversion in terms of yield and production cost as the process can be consequently conducted at higher substrate loadings.
High-frequency SiPM readout advances measured coincidence time resolution limits in TOF-PET

Scintillator based radiation detectors readout by SiPMs successively break records in their reached time resolution. Nevertheless, new challenges in time of flight positron emission tomography (TOF-PET) and high energy physics are setting unmatched goals in the 10 ps range. Recently it was shown that high frequency (HF) readout of SiPMs significantly improves the measured single photon time resolution (SPTR), allowing to evaluate the intrinsic performance of large area devices; e.g. FBK NUV-HD SiPMs of mm2 area and 40 m single photon avalanche diode (SPAD) size achieve 90 ps FWHM. In TOF-PET such readout allows to lower the leading edge detection threshold, so that the fastest photons produced in the crystal can be utilized. This is of utmost importance if a high SPTR and prompt Cherenkov light generated by the hot-recoil electron upon 511 keV photo-absorption should improve timing. This paper shows that high-frequency bipolar transistor readout of state-of-the-art SiPMs coupled to high-performance scintillators can substantially improve the best achievable coincidence time resolution (CTR) in TOF-PET. In this context a CTR of 158 3 ps FWHM with mm3 BGO crystals coupled to FBK SiPMs is achieved. This faint Cherenkov signal is as well present in standard LSO scintillators, which together with low SPTR values (<90 ps FWHM) improves the CTR of mm3 LSO:Ce:Ca coupled to FBK NUV-HD mm2 with 25 m SPAD size to 61 2 ps FWHM using HF-electronics, as compared to 73 2 ps when readout by the NINO front-end ASIC. When coupling the LSO:Ce:Ca crystals to FBK NUV-HD SiPMs of mm2 and 40 m SPAD size, using HF-electronics, a CTR of even 58 3 ps for mm3 and 98 3 ps for mm3 is achieved. This new experimental data will allow to further discuss the timing limits in scintillator-based detectors.
Ultrasonography of the internal architecture of the superficial part of the masseter muscle in vivo

It is unclear whether the deep inferior tendon (DIT) is equally present in vivo, and little anatomical information is available regarding the existence and morphology of the DIT in healthy young subjects. The aim of this study was to characterize the DIT of the masseter muscle in healthy young subjects using ultrasonography and to compare the morphology of this tendon with previously reported data for healthy young subjects in order to provide the most‐effective injection methods for botulinum neurotoxin treatments of masseteric hypertrophy. This study investigated two fresh cadavers and 30 healthy subjects. Ultrasonography scanning in both longitudinal and transverse directions was applied to the masseter muscle. The DIT within the superficial part of the masseter was observed in both the fresh cadavers and the living subjects. The posterior region of the masseter muscle was compartmentalized (entirely covered) by the DIT in 26.7% of the specimens. The superficial part of the masseter muscle was divided by the DIT transversely and longitudinally into the superficial and deep muscle bellies in 35% and 38.3% of the specimens, respectively. The present findings suggest applying a DIT‐based injection technique under guidance by ultrasonography prior to treating masseteric hypertrophy. Clin. Anat. 32:446–452, 2019. © 2019 Wiley Periodicals, Inc.
Differential Bacterial Colonization and Biofilm Formation on Punctal Occluders

Dry eye is a common condition that is treated primarily by topical lubricants, immunomodulation, and a variety of punctal and canalicular plugs (occluders). Biofilm formation has been reported as an ongoing problem with the clinical use of occluders. In order to explore the role of biofilm formation on occluders, we tested the bacteria strain, Staphylococcus aureus, with three different types of occluders, DeltaR, OdysseyR, and AlphamedR. Scanning electron microscopy (SEM) of these occluders revealed a variation in surface appearance, with OdysseyR being the smoothest (but with grooves), followed by DeltaR, and AlphamedR. Exposing each type of occluder to dynamically grown bacterial cultures of S. aureus, a ~3 fold statistically significant difference in bacteria colonization between the OdysseyR and AlphamedR occluder and a ~2 fold higher trend between OdysseyR and DeltaR were detected. These quantitative results were also verified with SEM, showing extensive S. aureus colonization and biofilm formation on the surface of the OdysseyR occluder. The results also indicate that bacterial colonization readily occurs on all three types of occluders. The occluder with the smoothest but grooved surface (OdysseyR), displayed increased biofilm formation when compared to those with rougher surfaces.
Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats

Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid–induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.
Influence of exposure and vertical transmission of HIV-1 on the neuropsychomotor development in children.

INTRODUCTION Exposure to human immunodeficiency virus (HIV)-1 during pregnancy is a major risk factor for neurodevelopmental delay and deleterious effects in children. However, limited information about these conditions exists in poor geographical areas in Brazil. Prevention of vertical transmission of HIV-1 is dealt differently in different regions of the country and in poorer areas it is more difficult to evaluate the impact of the prevention methods. The outcomes of the exposure to HIV-1 and the impact of vertical HIV-1 transmission on neuropsychomotor development was evaluated for the first time in children born to HIV-infected mothers in the North region of Brazil, where the majority of the population has poor access to health services. METHODS Sixty children born to HIV-1-infected mothers (case group) and 58 born to non-infected mothers (control group) were followed for the first 12 months of life in a prospective case-control study. Neuropsychomotor development was assessed using the Denver II test. RESULTS Suspected neuropsychomotor developmental delays were more frequent in the case group (33.3%), namely in language (38.9%) and gross motor skills (27.8%). These delays were reversed in most children after 12 months of life due to therapeutic intervention. The delays were not reversed in three children, all of whom belonged to the case group. Only one of these was infected with HIV-1, and this child had the poorest neuropsychomotor outcomes. CONCLUSIONS Maternal HIV-1 infection negatively affected the neuropsychomotor development in children, although other factors may have played a role.
Reverse Cholesterol Transport and Atherosclerosis.

Despite improvements in atherosclerotic cardiovascular disease (ASCVD) by targeting reduction of apoBcontaining lipoproteins, ASCVD remains the leading cause of death. In addition, participants randomized to the intervention arms of contemporary lipid-lowering clinical trials continue to experience ASCVD events at alarming and unacceptable rates. Recent efforts have begun to focus on the active removal of cholesterol from the arterial wall, termed reverse cholesterol transport (RCT). The RCT process is an endogenous mechanism that allows cells to export cholesterol and maintain homeostasis. It has become increasingly clear from animal and human studies that impaired RCT can lead to accelerated atherosclerosis and, vice versa, enhanced RCT can limit or prevent atherosclerosis.
Autonomous Goal Striving Promotes a Nonlimited Theory About Willpower

People who believe that willpower is not limited exhibit higher self-regulation and well-being than people who believe that willpower is a limited resource. So far, only little is known about the antecedents of people’s beliefs about willpower. Three studies examine whether autonomous goal striving promotes the endorsement of a nonlimited belief and whether this relationship is mediated by vitality, the feeling of being awake and energetic. Study 1 (n = 208) showed that autonomous goal striving predicts a change in willpower beliefs over 4 months and that this change is mediated by vitality. Study 2 (n = 92) replicated this finding using experience sampling assessments of vitality. Experimental Study 3 (n = 243) showed that inducing an autonomous mind-set enhances people’s endorsement of a nonlimited belief by fostering vitality. The studies support the idea that what people believe about willpower depends, at least in part, on recent experiences with tasks as being energizing or draining.
Targeting strategies of liposomal subunit vaccine delivery systems to improve vaccine efficacy

Abstract Liposomes are versatile delivery systems and immunological adjuvants that not only can load various antigens, such as proteins, peptides, nucleic acids and carbohydrates, but also can combine them with immunostimulators. Liposomes have great potential in the development of new types of vaccines, and much effort has been devoted to enhancing vaccine efficacy in recent years. Different types of immune cells such as macrophages and dendritic cells play an important role in the immune response and in preventing or treating cancer, allergy or many other infectious diseases. Targeting liposome-based delivery systems to certain immune cells and organs is one of the most effective measures in such treatments. Extensive research has shown that liposomes combined with immunostimulators or modified with pattern recognition receptor ligands can target various immune cells and the lymphatic system, thus not only inducing and promoting the desired immune response but also decreasing adverse effects throughout the body and avoiding targeting irrelevant cell types or tissues. Therefore, in this review, we outline some targeting strategies that can be adopted in the design of liposomal vaccines to improve vaccine efficacy, and we summarise the related liposome-based vaccine applications in several diseases. These applications have great potential to treat or prevent some infectious and intractable diseases.
Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency

Significance Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5-anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with our findings, we observed that treatment with a 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology. Neutropenia represents an important problem in patients with genetic deficiency in either the glucose-6-phosphate transporter of the endoplasmic reticulum (G6PT/SLC37A4) or G6PC3, an endoplasmic reticulum phosphatase homologous to glucose-6-phosphatase. While affected granulocytes show reduced glucose utilization, the underlying mechanism is unknown and causal therapies are lacking. Using a combination of enzymological, cell-culture, and in vivo approaches, we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-KM hexokinases, which catalyze the first step in glycolysis in most tissues. We show that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol, a compound normally present in human plasma, by side activities of ADP-glucokinase and low-KM hexokinases. Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (∼3 mM) that strongly inhibit hexokinase activity. In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death. Treating G6PC3-deficient mice with an inhibitor of the kidney glucose transporter SGLT2 to lower their blood level of 1,5-anhydroglucitol restored a normal neutrophil count, while administration of 1,5-anhydroglucitol had the opposite effect. In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.