Miracle-dz/UniFAR-FTUs huggingface dataset:
Bioprinted Skin Recapitulates Normal Collagen Remodeling in Full-thickness Wounds.

Over 1 million burn injuries are treated annually in the United States, and current tissue engineered skin fails to meet the need for full-thickness replacement. Bioprinting technology has allowed fabrication of full-thickness skin and has demonstrated the ability to close full-thickness wounds. However, analysis of collagen remodeling in wounds treated with bioprinted skin has not been reported. The purpose of this study is to demonstrate the utility of bioprinted skin for epidermal barrier formation and normal collagen remodeling in full-thickness wounds. Human keratinocytes, melanocytes, fibroblasts, dermal microvascular endothelial cells, follicle dermal papilla cells, and adipocytes were suspended in fibrinogen bioink and bioprinted to form a tri-layer skin structure. Bioprinted skin was implanted onto 2.5 x 2.5cm full-thickness excisional wounds on athymic mice, compared with wounds treated with hydrogel only or untreated wounds. Total wound closure, epithelialization, and contraction was quantified, and skin samples were harvested at 21 days for histology. Picrosirius red staining was used to quantify collagen fiber orientation, length, and width. Immunohistochemical (IHC) staining was performed to confirm epidermal barrier formation, dermal maturation, vascularity, and human cell integration. All bioprinted skin treated wounds closed by day 21, compared with open control wounds. Wound closure in bioprinted skin treated wounds was primarily due to epithelialization. In contrast, control hydrogel and untreated groups had sparse wound coverage and incomplete closure driven primarily by contraction. Picrosirius red staining confirmed a normal basket weave collagen organization in bioprinted skin-treated wounds compared with parallel collagen fibers in hydrogel only and untreated wounds. IHC staining at day 21 demonstrated the presence of human cells in the regenerated dermis, the formation of a stratified epidermis, dermal maturation, and blood vessel formation in bioprinted skin, none of which were present in control hydrogel treated wounds. Bioprinted skin accelerated full-thickness wound closure by promoting epidermal barrier formation, without increasing contraction. This healing process is associated with human cells from the bioprinted skin laying down a healthy, basket-weave collagen network. The remodeled skin is phenotypically similar to human skin and composed of a composite of graft and infiltrating host cells.
Pneumothorax rates in CT-Guided lung biopsies: A comprehensive systematic review and Meta-Analysis of risk factors.

OBJECTIVES This systematic review and meta-analysis investigated risk factors for pneumothorax following computed tomography-guided percutaneous transthoracic lung biopsy. METHODS A systematic search of nine literature databases between inception to September 2019 for eligible studies was performed. RESULTS 36 articles were included with 2,3104 patients. The overall pooled incidence for pneumothorax was 25.9% and chest drain insertion was 6.9%. Pneumothorax risk was significantly reduced in the lateral decubitus position where the biopsied lung was dependent compared to a prone or supine position (OR:3.15). In contrast, pneumothorax rates were significantly increased in the lateral decubitus position where the biopsied lung was non-dependent compared to supine (OR:2.28) or prone position (OR:3.20). Other risk factors for pneumothorax included puncture site up compared to down through a purpose-built biopsy window in the CT table (OR:4.79), larger calibre guide/needles (≤18G vs >18G: OR 1.55), fissure crossed (OR:3.75), bulla crossed (OR:6.13), multiple pleural punctures (>1 vs 1: OR:2.43), multiple non-coaxial tissue sample (>1 vs 1: OR 1.99), emphysematous lungs (OR:3.33), smaller lesions (<4 cm vs 4 cm: OR:2.09), lesions without pleural contact (OR:1.73) and deeper lesions (≥3 cm vs <3cm: OR:2.38). CONCLUSIONS This meta-analysis quantifies factors that alter pneumothorax rates, particularly with patient positioning, when planning and performing a CT guided lung biopsy to reduce pneumothorax rates. ADVANCES IN KNOWLEDGE Positioning patients in lateral decubitus with the biopsied lung dependent, puncture site down with a biopsy window in the CT table, using smaller calibre needles and using coaxial technique if multiple samples are needed are associated with a reduced incidence of pneumothorax.
Sex-Specific Differential Responses of Circulating Biomarkers in Obstructive Sleep Apnea Treatment: a Post-hoc Analysis of a Randomized Controlled Trial.

RATIONALE Sex-specific changes of cardiovascular biomarkers in response to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) is limited. OBJECTIVE We hypothesize a differential sex-specific cardiovascular biomarker response with CPAP therapy for OSA. METHODS Participants with moderate-severe OSA(apnea-hypopnea index, AHI ≥ 15) were randomized to CPAP versus sham completing polysomnography and collection of biomarkers of inflammation (myeloperoxidase, fibrinogen, paroxonase, interleukin(IL)-6, IL-6 soluble receptor, aryl esterase, oxidized LDL, lipoprotein A, plasminogen activator inhibitor-1, and F2-isoprostane urine to creatinine ratio) and vascular measures at baseline and 8-weeks of therapy with either CPAP (n=72) or sham (n=70). Post-hoc secondary analyses of sex-study arm interaction relative to change in inflammatory biomarkers were evaluated via linear regression with adjustment for baseline biomarker value, age, race, body mass, index, waist circumference, and CPAP adherence. Interactions were further evaluated via sex-stratified analyses. RESULTS 149 participants were aged 50.8±11.7 years, 55% male, 55% white with median AHI 26.3 (IQR:13-37). There were substantialinteractions between study arm and sex for myeloperoxidase, paraoxonase, and fibrinogen (p=0.03, p=0.03, and p=0.08, respectively). No significant interactions were found for the vascular measures. Estimates were similar but with decreased power in sex-stratified analyses with decreased biomarkers in women and increased biomarkers in men. CONCLUSIONS Differential sex-specific responses to CPAP therapy for OSA were observed for circulating inflammatory biomarkers which persisted after adjustment for confounders. These findings set the stage for validation studies and, if confirmed, biochemical pathway elucidatoin to inform sex-specific personalized treatment approaches. Clinical trial registered with ClinicalTrials.gov (NCT00607893).
Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.
New Proposal for Size and Size-Distribution Evaluation of Nanoparticles Synthesized via Ultrasonic Spray Pyrolysis Using Search Algorithm Based on Image-Processing Technique

Nanoparticle properties are correlated to their size, size distribution, and shape; it is essential to accurately measure these features in the field of nanoscience. In this study, silver nanoparticles (AgNPs) were synthesized with the ultrasonic-spray-pyrolysis (USP) method from a water solution of silver nitrate. The synthesized AgNPs were characterized by Dynamic Light Scattering (DLS) analysis and Scanning Electron Microscopy (SEM) to reveal their size and size distribution. A search algorithm based on an image-processing technique to obtain particle size and particle-size distribution from SEM micrographs is proposed. In order to obtain more quantitative information and data with respect to the morphology of particles synthesized under different process parameters, SEM micrographs with a nonhomogeneous background contrast were examined via image-processing techniques in MATLAB. Due to the inhomogeneous contrast of SEM micrographs, defining an overall threshold value was insufficient in the detection of whole nanoparticles. Thus, subimages were directly created according to the maximum and minimum particle size specified by the user to determine local threshold values. The obtained results were automatically combined to represent both particle dimension and location in the SEM micrographs. We confirmed that the results of our DLS analysis, theoretical calculation, and image-processing technique were correlated with our expected results.
Relationship between urate within tophus and bone erosion according to the anatomic location of urate deposition in gout

Abstract The aim of this study was to measure the urate volume within tophus and bone erosion volume using dual-energy computed tomography in patients with tophaceous gout. Furthermore, our study aims to quantitatively analyze the relationship between monosodium urate (MSU) crystal deposition and bone erosion according to the anatomic location of urate deposition. Seventy-seven subjects with chronic gout were positively identified for the presence of urate deposition. Only 27 subjects identified for the presence of urate in contact with bone erosion were included in this study. The urate volumes and associated erosion volumes were measured. The relationships between urate within tophus and bone erosion were separately analyzed according to the anatomic location of urate deposition. Twenty-seven subjects were all male (100%) with a median (interquartile range, IQR) age of 52 (45–61) years. From all the subjects, 103 tophi depositions were identified in contact with bone erosion, including 58/103 tophi that contained an intraosseous component and 45/103 nonintraosseous tophi. Tophi containing intraosseous components were larger than nonintraosseous tophi (urate volume: median [IQR] 45.64 [4.79–250.89] mm3 vs 19.32 [6.97–46.71] mm3, P = .035) and caused greater bone erosion (erosion volume: 249.03 [147.08–845.33] mm3 vs 69.07 [32.88–111.24] mm3, P < .001). Almost all erosion volumes were larger than urate volumes in nonperiarticular tophi, in contrast to most erosion volumes, which were less than urate volumes in the tophi that contained a periarticular component (odds ratio, 95% confidence interval: 74.00, 14.70–372.60; P < .001). Urate volume and erosion volume demonstrated positive correlations in intraosseous tophi, intraosseous-intra-articular-periarticular tophi, and intraosseous-intra-articular tophi (rs = 0.761, rs = 0.695, rs = 0.629, respectively, P < .05). MSU crystal deposition shows a promoting effect on the development of bone erosions in varying degrees, associated with the location of MSU crystals deposited in the joints. The intraosseous tophi contribute the most to bone erosions, followed by intra-articular tophi, and periarticular tophi.
Uncovering Matrix Effects on Lipid Analyses in MALDI Imaging Mass Spectrometry Experiments.

The specific matrix used in matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) can have an effect on the molecules ionized from a tissue sample. The sensitivity for distinct classes of biomolecules can vary when employing different MALDI matrices. Here, we compare the intensities of various lipid sub-classes measured by Fourier transform ion cyclotron resonance (FT-ICR) IMS of murine liver tissue when using 9-Aminoacridine (9AA), 5-Chloro-2-mercaptobenzothiazole (CMBT), 1,5-Diaminonaphthalene (DAN), 2,5-Dihydroxyacetophenone (DHA), and 2,5-Dihydroxybenzoic acid (DHB). Principal component analysis and receiver operating characteristic curve analysis revealed significant matrix effects on the relative signal intensities observed for different lipid sub-classes and adducts. Comparison of spectral profiles and quantitative assessment of the number and intensity of species from each lipid sub-class showed that each matrix produces unique lipid signals. In positive ion mode, matrix application methods played a role in the MALDI analysis for different cationic species. Comparisons of different methods for the application of DHA showed a significant increase in the intensity of sodiated and potassiated analytes when using an aerosol sprayer. In negative ion mode, lipid profiles generated using DAN were significantly different than all other matrices tested. This difference was found to be driven by modification of phosphatidylcholines during ionization that enables them to be detected in negative ion mode. These modified phosphatidylcholines are isomeric with common phosphatidylethanolamines confounding MALDI IMS analysis when using DAN. These results show an experimental basis of MALDI analyses when analyzing lipids from tissue and allow for more informed selection of MALDI matrices when performing lipid IMS experiments.
Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

Pericytes are branched cells located in the wall of capillary blood vessels that are found throughout the body, embedded within the microvascular basement membrane and wrapping endothelial cells, with which they establish a strong physical contact. Pericytes regulate angiogenesis, vessel stabilization, and contribute to the formation of both the blood-brain and blood-retina barriers by Angiopoietin-1/Tie-2, platelet derived growth factor (PDGF) and transforming growth factor (TGF) signaling pathways, regulating pericyte-endothelial cell communication. Human pericytes that have been cultured for a long period give rise to multilineage progenitor cells and exhibit mesenchymal stem cell (MSC) features. We focused our attention on the roles of pericytes in brain and ocular diseases. In particular, pericyte involvement in brain ischemia, brain tumors, diabetic retinopathy, and uveal melanoma is described. Several molecules, such as adenosine and nitric oxide, are responsible for pericyte shrinkage during ischemia-reperfusion. Anti-inflammatory molecules, such as IL-10, TGFβ, and MHC-II, which are increased in glioblastoma-activated pericytes, are responsible for tumor growth. As regards the eye, pericytes play a role not only in ocular vessel stabilization, but also as a stem cell niche that contributes to regenerative processes in diabetic retinopathy. Moreover, pericytes participate in melanoma cell extravasation and the genetic ablation of the PDGF receptor reduces the number of pericytes and aberrant tumor microvessel formation with important implications for therapy efficacy. Thanks to their MSC features, pericytes could be considered excellent candidates to promote nervous tissue repair and for regenerative medicine.
The Nucleus Accumbens Core Is Necessary for Responding to Incentive But Not Instructive Stimuli

An abundant literature has highlighted the importance of the nucleus accumbens core (NAcC) in behavioral tasks dependent on external stimuli. Yet, some studies have also reported the absence of involvement of the NAcC in stimuli processing. We aimed at comparing, in male rats, the underlying neuronal determinants of incentive and instructive stimuli in the same task. We developed a variant of a GO/NOGO task that reveals important differences in these two types of stimuli. An abundant literature has highlighted the importance of the nucleus accumbens core (NAcC) in behavioral tasks dependent on external stimuli. Yet, some studies have also reported the absence of involvement of the NAcC in stimuli processing. We aimed at comparing, in male rats, the underlying neuronal determinants of incentive and instructive stimuli in the same task. We developed a variant of a GO/NOGO task that reveals important differences in these two types of stimuli. The incentive stimulus invites the rat to engage in the task sequence. Once the rat has decided to initiate a trial, it remains engaged in the task until the end of the trial. This task revealed the differential contribution of the NAcC to responding to different types of stimuli: responding to the incentive stimulus depended on NAcC AMPA/NMDA and dopamine D1 receptors, but the retrieval of the response associated with the instructive stimuli (lever pressing on GO, withholding on NOGO) did not. Our electrophysiological study showed that more NAcC neurons responded more strongly to the incentive than the instructive stimuli. Furthermore, when animals did not respond to the incentive stimulus, the induced excitation was suppressed for most projection neurons, whereas interneurons were strongly activated at a latency preceding that found in projection neurons. This work provides insight on the underlying neuronal processes explaining the preferential implication of the NAcC in deciding whether and when to engage in reward-seeking rather than to decide which action to perform. SIGNIFICANCE STATEMENT The nucleus accumbens core (NAcC) is essential to process information carried by reward-predicting stimuli. Yet, stimuli have distinct properties: incentive stimuli orient the attention toward reward-seeking, whereas instructive stimuli inform about the action to perform. Our study shows that, in male rats, NAcC perturbation with glutamate or dopamine antagonists impeded responses to the incentive but not to the instructive stimulus. NAcC neuronal recordings revealed a stronger representation of incentive than instructive stimuli. Furthermore, we found that interneurons are recruited when rats fail to respond to incentive stimuli. This work provides insight on the underlying neuronal processes explaining the preferential implication of the NAcC in deciding whether and when to engage in reward-seeking rather than to decide which action to perform.
Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis

The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.
Role of Baseline and Post-Therapy 18F-FDG PET in the Prognostic Stratification of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated with Radium-223

Radium-223 dichloride (Ra223) represents the unique bone-directed treatment option that shows an improvement in overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC). However, there is an urgent need for the identification of reliable biomarkers to non-invasively determine its efficacy (possibly improving patients’ selection or identifying responders’ after therapy completion). 18F-Fluorodeoxyglucose (FDG)-avidity is low in naïve prostate cancer, but it is enhanced in advanced and chemotherapy-refractory mCRPC, providing prognostic insights. Moreover, this tool showed high potential for the evaluation of response in cancer patients with bone involvement. For these reasons, FDG Positron Emission Tomography (FDG-PET) might represent an effective tool that is able to provide prognostic stratification (improving patients selection) at baseline and assessing the treatment response to Ra223. We conducted a retrospective analysis of 28 mCRPC patients that were treated with Ra223 and submitted to bone scan and FDG-PET/CT for prognostic purposes at baseline and within two months after therapy completion. The following parameters were measured: number of bone lesions at bone scan, SUVmax of the hottest bone lesion, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). In patients who underwent post-therapy 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT), (20/28), PET Response Criteria in Solid Tumors (PERCIST), and European Organization for Research and Treatment of Cancer (EORTC) criteria were applied to evaluate the metabolic treatment response. The difference between end of therapy and baseline values was also calculated for Metabolic Tumor Volume (MTV), TLG, prostate-specific antigen (PSA), alkaline phosphatase (AP), and lactate dehydrogenase (LDH) (termed deltaMTV, deltaTLG, deltaPSA, deltaAP and deltaLDH, respectively). Predictive power of baseline and post-therapy PET- and biochemical-derived parameters on OS were assessed by Kaplan–Meier, univariate and multivariate analyses. At baseline, PSA, LDH, and MTV significantly predicted OS. However, MTV (but not PSA nor LDH) was able to identify a subgroup of patients with worse prognosis, even after adjusting for the number of lesions at bone scan (which, in turn, was not an independent predictor of OS). After therapy, PERCIST criteria were able to capture the response to Ra223 by demonstrating longer OS in patients with partial metabolic response. Moreover, the biochemical parameters were outperformed by PERCIST in the post-treatment setting, as their variation after therapy was not informative on long term OS. The present study supports the role of FDG-PET as a tool for patient’s selection and response assessment in mCRPC patients undergoing Ra223 administration.
Small Area Estimation and Hotspot Identification of Opioid Use Disorder among Military Veterans Living in the Southern United States

Background The purpose of this study was to estimate opioid use disorder prevalence rates at the county level among veterans in Alabama and to determine hotspots of said rates. Methods By combining data from the National Survey on Drug Use and Health and the American Community Survey, we developed a mixed-effects generalized linear model of opioid use disorder and modeled probabilities onto veteran-specific population counts at the county level in Alabama. Results The average model-based estimate for opioid use disorder prevalence among veterans in Alabama from 2015 to 2017 was 0.79% (SD = 0.16), with a minimum of 0.52% (i.e., Lowndes county, Alabama) and a maximum of 1.10% (Dale county, Alabama). Hotspot analysis revealed a significant cluster of “high-high” veteran opioid use disorder prevalence in neighboring Marion, Winston, and Cullman counties. Conclusions The application of the statistical technique presented in this study can provide feasible, cost-effective, and practical county-level prevalence estimates of veteran-specific opioid use disorder and should be widely applied by states and counties so that they can more accurately and efficiently allocate resources to caring for veterans with an opioid use disorder.