Miracle-dz/UniFAR-FTUs huggingface dataset:
Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3β- and 11β-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.
AP-1 subunits converge promiscuously at enhancers to potentiate transcription

The AP-1 transcription factor (TF) dimer contributes to many biological processes and environmental responses. AP-1 can be composed of many interchangeable subunits. Unambiguously determining the binding locations of these subunits in the human genome is challenging because of variable antibody specificity and affinity. Here, we definitively establish the genome-wide binding patterns of five AP-1 subunits by using CRISPR to introduce a common antibody tag on each subunit. We find limited evidence for strong dimerization preferences between subunits at steady state and find that, under a stimulus, dimerization patterns reflect changes in the transcriptome. Further, our analysis suggests that canonical AP-1 motifs indiscriminately recruit all AP-1 subunits to genomic sites, which we term AP-1 hotspots. We find that AP-1 hotspots are predictive of cell type–specific gene expression and of genomic responses to glucocorticoid signaling (more so than super-enhancers) and are significantly enriched in disease-associated genetic variants. Together, these results support a model where promiscuous binding of many AP-1 subunits to the same genomic location play a key role in regulating cell type–specific gene expression and environmental responses.
Regarding Zha et al. "A bibliometric analysis of global research production pertaining to diabetic foot ulcers in the past ten years".

Regarding the article by Zha et al (1), “A bibliometric analysis of global research production pertaining to diabetic foot ulcers in the past ten years,” the authors said that, “All of the reference data used in our study were retrieved from the WoSCC [Web of Science Core Collection] and the data retrieval strategy was topic: diabetic foot ulcer* OR diabetic foot wound*; time span: 2007 to 2018 (retrieved data March 22, 2018); and document type: article, review, proceedings paper. A total of 4580 references were retrieved. ” Diabetic foot ulcer* or diabetic foot
How Do Inflammatory Mediators, Immune Response and Air Pollution Contribute to COVID-19 Disease Severity? A Lesson to Learn

Inflammatory and immune processes are defensive mechanisms that aim to remove harmful agents. As a response to infections, inflammation and immune response contribute to the pathophysiological mechanisms of diseases. Coronavirus disease 2019 (COVID-19), whose underlying mechanisms remain not fully elucidated, has posed new challenges for the knowledge of pathophysiology. Chiefly, the inflammatory process and immune response appear to be unique features of COVID-19 that result in developing a hyper-inflammatory syndrome, and air pollution, the world’s largest health risk factor, may partly explain the behaviour and fate of COVID-19. Understanding the mechanisms involved in the progression of COVID-19 is of fundamental importance in order to avoid the late stage of the disease, associated with a poor prognosis. Here, the role of the inflammatory and immune mediators in COVID-19 pathophysiology is discussed.
An efficient R1ρ dispersion imaging method for human knee cartilage using constant magnetization prepared turbo‐FLASH

This work aimed to develop an efficient R1ρ dispersion imaging method for clinical studies of human knee cartilage at 3 T. Eight constant magnetizations (Mprep) were prepared by tailoring both the duration and amplitude (ω1) of a fully refocused spin‐lock preparation pulse. The limited Mprep dynamic range was expanded by the measure, equivalent to that with ω1 = ∞, from the magic angle location in the deep femoral cartilage. The developed protocol with Mprep = 60% was demonstrated on one subject's bilateral and two subjects' unilateral asymptomatic knees. The repeatability of the proposed protocol was estimated by two repeated scans with a three‐month gap for the last two subjects. The synthetic R1ρ and R2 derived from R1ρ dispersions were compared with the published references using state‐of‐the‐art R1ρ and R2 mapping (MAPSS). The proposed protocol demonstrated good (<5%) repeatability quantified by the intra‐ and intersubject coefficients of variation in the femoral and tibial cartilage. The synthetic R1ρ (1/s) and the references were comparable in the femoral (23.0 ± 5.3 versus 24.1 ± 3.8, P = 0.67) and the tibial (29.1 ± 8.8 versus 27.1 ± 5.1, P = 0.62), but not the patellar (16.5 ± 4.9 versus 22.7 ± 1.6, P < 0.01) cartilage. The same trends were also observed for the current and the previous R2. In conclusion, the developed R1ρ dispersion imaging scheme has been revealed to be not only efficient but also robust for clinical studies of human knee cartilage at 3 T.
Staphylococcus aureus Isolated from Ruminants with Mastitis in Northern Greece Dairy Herds: Genetic Relatedness and Phenotypic and Genotypic Characterization

Staphylococcus aureus is the most common mastitis-related pathogen in dairy cattle, goats, and sheep worldwide. However, the population structure and genomic characteristics of mastitis-associated S. aureus in small ruminants are limited. Furthermore, the genotypic and phenotypic characteristics involved in the pathogenicity of S. aureus have been thoroughly defined, yet their association with the severity of mastitis is not fully established. Here, we performed genotyping by pulsed-field gel electrophoresis (PFGE) and spa analyses to assess the genetic diversity and relatedness of 162 S. aureus strains recovered from clinical mastitis (CM) and subclinical mastitis (SCM) cases from goats, sheep, and bovines. PFGE analysis revealed 108 distinguishable pulsotypes and 3 main clusters that comprised isolates from the three host species, while according to spa typing, 32 different spa types were identified. Genotypic analysis revealed a spreading of genetically related or indistinguishable S. aureus strains among ovine, caprine, and bovine farms of distant geographical regions. In total, 28 different staphylococcal enterotoxin (SE) gene profiles were observed, revealing a diverse range of SE genes among isolates. By evaluating the antimicrobial resistance, we found low phenotypic antimicrobial resistance among all ruminant isolates. We also performed multiple correspondence analysis, which indicated that the presence of the sec gene, biofilm production, and high autoaggregation ability are associated with CM cases.
Branched High Aspect Ratio Nanostructures Fabricated by Focused Helium Ion Beam Induced Deposition of an Insulator

Helium ion beam induced deposition using the gaseous precursor pentamethylcyclopentasiloxane is employed to fabricate high aspect ratio insulator nanostructures (nanopillars and nanocylinders) that exhibit charge induced branching. The branched nanostructures are analyzed by transmission electron microscopy. It is found that the side branches form above a certain threshold height and that by increasing the flow rate of the precursor, the vertical growth rate and branching phenomenon can be significantly enhanced, with fractalesque branching patterns observed. The direct-write ion beam nanofabrication technique described herein offers a fast single-step method for the growth of high aspect ratio branched nanostructures with site-selective placement on the nanometer scale.
CHEMICAL COMPOSITION AND ANTIBACTERIAL ACTIVITIES FROM THE ESSENTIAL OILS OF MYRTACEAE SPECIES PLANTED IN BRAZIL

The essential oils of seven Myrtaceae species were investigated for its chemical composition and antibacterial activity. The volatile oils were characterized by a high content of monoterpenoids of which 1,8-cineole (88.0, 65.0 and 77.0% for Melaleuca hypericifolia, Callistemon viminalis and Callistemon citrinus respectively), terpinen-4-ol (47.0 and 49.8% for Melaleuca thymifolia and Callistemon polandii respectively) and α-pinene (54.5% for Kunzea ericoides) were the major components. The oil from M. linariifolia was characterized by a high concentration of methyleugenol (87.2%). The oil from Melaleuca thymifolia was the most active, exhibiting high antimicrobial activity against all tested bacteria.
A New Generation of Functional Tagged Proteins for HIV Fluorescence Imaging

During the last decade, there was a marked increase in the development of tools and techniques to study the molecular mechanisms of the HIV replication cycle by using fluorescence microscopy. Researchers often apply the fusion of tags and fluorophores to viral proteins, surrogate proteins, or dyes to follow individual virus particles while they progress throughout infection. The inclusion of such fusion motifs or surrogates frequently disrupts viral infectivity or results in a change of the wild-type phenotype. Here, we detail the construction and functional characterization of two new constructs where we fused fluorescent proteins to the N-terminus of HIV-1 Integrase. In the first, IN is recruited into assembling particles via a codon optimized Gag to complement other viral constructs, while the second is fused to a Gag-Pol expression vector fully capable of integration. Our data shows that N-terminal tagged IN is functional for integration by both recovery of integration of catalytically inactive IN and by the successful infectivity of viruses carrying only labeled IN. These tools will be important to study the individual behavior of viral particles and associate such behavior to infectivity.
Glycogen supercompensation is due to increased number, not size, of glycogen particles in human skeletal muscle

What is the central question of this study? Glycogen supercompensation after glycogen‐depleting exercise can be achieved by consuming a carbohydrate‐enriched diet, but the associated effects on the size, number and localization of intramuscular glycogen particles are unknown. What is the main finding and its importance? Using transmission electron microscopy to inspect individual glycogen particles visually, we show that glycogen supercompensation is achieved by increasing the number of particles while keeping them at submaximal sizes. This might be a strategy to ensure that glycogen particles can be used fast, because particles that are too large might impair utilization rate.
Brain Function in Children with Obstructive Sleep Apnea: A Resting-State fMRI Study.

OBJECTIVE To explore the neural difference between children with obstructive sleep apnea (OSA) and healthy controls, together with the relation between this difference and cognitive dysfunction of children with OSA. METHODS Twenty children with OSA (7.2 ± 3.1 years, apnea hypopnea index (AHI): 16.5 ± 16.6 events/h) and 29 healthy controls (7.7 ± 2.8 years, AHI: 1.7 ± 1.2 events/h) were recruited and matched with age, gender, and handedness. All children underwent resting-state fMRI (rs-fMRI) and T1-wighted imaging. Some children were sedated for MRI scanning. We compared amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo) of children with OSA with those of healthy controls. During resting-state, the former reflects the intensity of the spontaneous neural activities, whereas the latter reflects temporal similarity of the spontaneous neural activities within a local brain region. Pearson correlation analysis was performed between these features of rs-fMRI and cognitive scores among children with OSA. RESULTS Compared with controls, children with OSA showed decreased ALFF in the left angular gyrus but increased ALFF in the right insula, and decreased ReHo in the left medial superior frontal gyrus, right lingual gyrus and left precuneus. Additionally, among children with OSA, the ReHo value in the right lingual gyrus was negatively correlated with FIQ and VIQ, whereas that in the left medial superior frontal gyrus was positively correlated with VIQ. CONCLUSIONS Children with OSA presented abnormal neural activities in some brain regions and impaired cognitive functions with the former possibly being the neural mechanism of the latter.
Validation of the Archived CERES Surface and Atmosphere Radiation Budget (SARB) at SGP

The CERES Surface and Atmosphere Radiation Budget (SARB) product (Charlock et al, 2002) includes the vertical profile of broadband SW, broadband LW, and 8-12 micron window (WN) fluxes; upwelling and downwelling at TOA, 70 hPa, 200 hPa, 500 hPa, and the surface; and for all-sky and clear-sky conditions. We test the archived CERES TRMM record of SARB for January-August 1998 and focus on discrepancies with ground-based measurements at SGP. The CERES SARB is generated by a highly modified Fu-Liou radiative transfer code (Fu and Liou, 1993). The most critical inputs for this application are cloud optical properties (fractional area, optical depth, particle size and phase, height of top, and estimate of geometrical thickness Minnis et al., 2002) from the narrowband VIRS imager. Numerous VIRS pixels (approx. 2km resolution at nadir) are matched to each of the large (approx. 20km) CERES broadband footprints (Wielicki et al, 1996). Other inputs include temperature and humidity from ECMWF (Rabier et al, 1998) , NCEP ozone profiles from SBUV and TOVS (Yang et al, 2001), aerosol optical thickness (AOT) from the Model for Atmospheric Transport and Chemistry (MATCH) aerosol assimilation (Collins et al., 2001) or alternately from the VIRS imager (Ignatov and Stowe, 2000). VIRS AOT is available for clear and partly cloudy ocean footprints during daylight; and only when viewing geometry renders a contribution from sunglint as unlikely. For other footprints, AOT is taken from MATCH. AOT is apportioned into fractions of dust (Tegan and Lacis, 1996), sea salt, sulfate, dust, soluble organic, insoluble organic, and soot (Hess et al., 1996) using the 6-hourly MATCH output. Tuned fluxes are retrieved by adjusting inputs to nudge computed TOA fluxes toward CERES observations (Rose et al, 1997). In clear conditions, the fields of humidity, surface skin temperature, surface albedo and AOT are adjusted to produce a closer match of computed and observed fluxes at TOA. When CERES footprints have clouds, the cloud optical thickness, fractional area within the footprint, and temperature of cloud top are adjusted by the tuning algorithm. Both tuned and untuned fluxes are archived, as are the respective adjustments to any parameters at the surface or within the atmosphere.
Doubly-Resonant Photonic Crystal Cavities for Efficient Second-Harmonic Generation in III–V Semiconductors

Second-order nonlinear effects, such as second-harmonic generation, can be strongly enhanced in nanofabricated photonic materials when both fundamental and harmonic frequencies are spatially and temporally confined. Practically designing low-volume and doubly-resonant nanoresonators in conventional semiconductor compounds is challenging owing to their intrinsic refractive index dispersion. In this work we review a recently developed strategy to design doubly-resonant nanocavities with low mode volume and large quality factor via localized defects in a photonic crystal structure. We built on this approach by applying an evolutionary optimization algorithm in connection with Maxwell equations solvers; the proposed design recipe can be applied to any material platform. We explicitly calculated the second-harmonic generation efficiency for doubly-resonant photonic crystal cavity designs in typical III–V semiconductor materials, such as GaN and AlGaAs, while targeting a fundamental harmonic at telecom wavelengths and fully accounting for the tensor nature of the respective nonlinear susceptibilities. These results may stimulate the realization of small footprint photonic nanostructures in leading semiconductor material platforms to achieve unprecedented nonlinear efficiencies.
Genetic impacts on thermostability of onco-lncRNA HOTAIR during the development and progression of endometriosis

HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications.
Real‐world evidence to support regulatory decision making: New or expanded medical product indications

There is increasing interest in utilizing real‐world data (RWD) to produce real‐world evidence (RWE) on the benefits and risks of medical products that could support regulatory approval decisions. The field of pharmacoepidemiology has a long history of focusing on data and evidence that would now be termed “real‐world,” including evidence from healthcare claims, registries, and electronic health records. However, several emerging trends over the past decade are converging to support the use of these and other RWD sources for approval decisions, and there are several recent examples and ongoing research that demonstrate how RWE may be used to support regulatory approval of new or expanded indications. The goal of this article is to review the current landscape and future directions of the use of RWE in this context. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).
Morphology and rheology of polysulfone/vectra-A950 blends

Blends of polysulfone (PSu) with a liquid crystalline copolyester (Vectra-A950; VA) have been prepared by melt mixing. Their morphology has been studied by scanning electron microscopy (SEM). Either blend specimens as obtained from the melt mixing or fibers drawn from the melt were used for the SEM analysis. Further information on the morphology of the blends was gained by extraction of the PSu phase with methylene chloride. Preliminary rheological characterization of the blends was made by measuring the viscosity curves at 290 and 300°C, with a capillary viscometer having a die of 1 mm diameter and L/D = 40. Finally, an attempt at improving the phase compatibility was made by synthesizing a copolyester, having the same structure of commercial VA, in the presence of preformed PSu and using the product as a possible compatibilizer. It was demonstrated that the blends are composed of two immiscible phase showing poor adhesion. The LCP droplets could, nevertheless, be deformed into oriented fibrils under elongational flow conditions. The LCP particles were shown to coalesce into large domains, and to migrate toward the outer layer of, e.g., extruded rods, under the influence of appropriate flow conditions, thus showing that there is a strong mutual influence between morphology and rheology of these materials. © 1995 John Wiley & Sons, Inc.
Does a Red House Affect Rhythms in Mice with a Corrupted Circadian System?

The circadian rhythms of body functions in mammals are controlled by the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus orchestrates subordinate oscillators. Time information is conveyed from the retina to the SCN to coordinate an organism’s physiology and behavior with the light/dark cycle. At the cellular level, molecular clockwork composed of interlocked transcriptional/translational feedback loops of clock genes drives rhythmic gene expression. Mice with targeted deletion of the essential clock gene Bmal1 (Bmal1−/−) have an impaired light input pathway into the circadian system and show a loss of circadian rhythms. The red house (RH) is an animal welfare measure widely used for rodents as a hiding place. Red plastic provides light at a low irradiance and long wavelength—conditions which affect the circadian system. It is not known yet whether the RH affects rhythmic behavior in mice with a corrupted circadian system. Here, we analyzed whether the RH affects spontaneous locomotor activity in Bmal1−/− mice under standard laboratory light conditions. In addition, mPER1- and p-ERK-immunoreactions, as markers for rhythmic SCN neuronal activity, and day/night plasma corticosterone levels were evaluated. Our findings indicate that application of the RH to Bmal1−/− abolishes rhythmic locomotor behavior and dampens rhythmic SCN neuronal activity. However, RH had no effect on the day/night difference in corticosterone levels.